Grantee Research Project Results
U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Research
Science to Achieve Results (STAR) Program
CLOSED - FOR REFERENCES PURPOSES ONLY
Organotypic Culture Models for Predictive Toxicology Center
Special Announcements
- Webinar Presentation (PDF) (27 pp,450 K)
This is the initial announcement of this funding opportunity.
Funding Opportunity Number: EPA-G2013-STAR-L1
Catalog of Federal Domestic Assistance (CFDA) Number: 66.509
Solicitation Opening Date: September 23, 2013
Solicitation Closing Date: January 23, 2014, 11:59:59 pm Eastern Time
Eligibility Contact: Ron Josephson (josephson.ron@epa.gov); phone: 703-308-0442
Electronic Submissions: Todd Peterson (peterson.todd@epa.gov); phone: 703-308-7224
Technical Contact: Barbara Klieforth (klieforth.barbara@epa.gov); phone: 703-347-8044
Access Standard STAR Forms (Forms and Standard Instructions Download Page)
View research awarded under previous solicitations (Funding Opportunities: Archive Page)
SUMMARY OF PROGRAM REQUIREMENTS
Synopsis of Program:
The U.S. Environmental Protection Agency (EPA), as part of its Science to Achieve Results (STAR) program, is seeking applications for research centers to investigate toxic effects of chemical substances in three-dimensional (3D) in vitro models, hereafter referred to as ‘organotypic culture models’ (OCMs). OCMs are tissue culture models that mimic in vivo tissue architecture through interactions of heterotypic cell types (e.g., epithelium-stroma) and extracellular matrices (ECM). They can be established from isolated cells or from tissue fragments harvested in vivo, and will bridge the gap between conventional monolayer cell cultures and whole-animal systems.
EPA is interested in the potential application of OCMs that mimic complex cell arrangements and physiologies, scalable from mid to higher throughput screening (HTS), and high-content screening (HCS) approaches. This solicitation seeks the formation of research centers that will guide the development and evaluation of OCMs that will accelerate translational research in predictive toxicology. Three dimensional tissue models may, for example, utilize animal cells combined with mechanical scaffolds or microfluidics devices. Under this solicitation, the successful applicant will lead a Center to craft OCMs that can recapitulate critical features of in vivo cellular organization and communication, cell-matrix interplay, morphogenetic processes and differentiation, physiology and chemical metabolism. Measures of success or progress should be described toward the application of OCMs for computational toxicology and reconstructing in vivo responses to environmental chemicals and nanomaterials to improve environmental health protection. As such, the OCMs should be scalable in support of medium to high throughput strategies or high-dimensional quantitative data collection, such as high content imaging, that respond to questions relevant to chemical risk assessment and management. For applications using human cells, it is preferred that the cells are already available or derive from available cell lines. Under EPA Regulation 40 CFR Part 26 (Protection of Human Subjects), using pre-existing human cell lines is not considered human subjects research.
This solicitation provides the opportunity for the submission of applications for projects that may involve human subjects research. Human subjects research supported by the EPA is governed by EPA Regulation 40 CFR Part 26 (Protection of Human Subjects). This includes the Common Rule at subpart A and prohibitions and additional protections for pregnant women and fetuses, nursing women, and children at subparts B, C, and D. Research meeting the regulatory definition of intentional exposure research found in subpart B is prohibited by that subpart in pregnant women, nursing women, and children. Research meeting the regulatory definition of observational research found in subparts C and D is subject to the additional protections found in those subparts for pregnant women and fetuses (subpart C) and children (subpart D). All applications must include a Human Subjects Research Statement (HSRS, as described in Section IV.B.8), and if the project involves human subjects research, it will be subject to an additional level of review prior to funding decisions being made as described in Sections V.C and V.D of this solicitation.
Guidance and training for investigators conducting EPA-funded research involving human subjects may be obtained here:
Ethics, Regulations, and Policies
Human Subjects Research at the Environmental Protection Agency: Ethical Standards and Regulatory Requirements
Award Information:
Anticipated Type of Award: Grant
Estimated Number of Awards: Approximately 3 awards
Anticipated Funding Amount: Approximately $18 million total for all awards
Potential Funding per Award: Up to a total of $6 million, including direct and indirect costs, with a maximum duration of 4 years. Cost-sharing is not required. Proposals with budgets exceeding the total award limits will not be considered.
Eligibility Information:
Public nonprofit institutions/organizations (includes public institutions of higher education and hospitals) and private nonprofit institutions/organizations (includes private institutions of higher education and hospitals) located in the U.S., state and local governments, Federally Recognized Indian Tribal Governments, and U.S. territories or possessions are eligible to apply. See full announcement for more details.
Application Materials:
To apply under this solicitation, use the application package available at Grants.gov (for further submission information see Section IV.E. “Submission Instructions and other Submission Requirements”). The necessary forms for submitting a STAR application will be found on the National Center for Environmental Research (NCER) web site, Forms and Standard Instructions Download Page.
If your organization is not currently registered with Grants.gov, you need to allow approximately one month to complete the registration process. Please note that the registration process also requires that your organization have a DUNS number and a current registration with the System for Award Management (SAM) and the process of obtaining both could take a month or more. Applicants must ensure that all registration requirements are met in order to apply for this opportunity through grants.gov and should ensure that all such requirements have been met well in advance of the submission deadline. This registration, and electronic submission of your application, must be performed by an authorized representative of your organization.
If you do not have the technical capability to utilize the Grants.gov application submission process for this solicitation, send a webmail message at least 15 calendar days before the submission deadline to assure timely receipt of alternate submission instructions. In your message provide the funding opportunity number and title of the program, specify that you are requesting alternate submission instructions, and provide a telephone number, fax number, and an email address, if available. Alternate instructions will be emailed whenever possible. Any applications submitted through alternate submission methods must comply with all the provisions of this Request for Applications (RFA), including Section IV, and be received by the solicitation closing date identified above.
Agency Contacts:
Eligibility Contact: Ron Josephson (josephson.ron@epa.gov); phone: 703-308-0442
Electronic Submissions: Todd Peterson (peterson.todd@epa.gov); phone: 703-308-7224
Technical Contact: Barbara Klieforth (klieforth.barbara@epa.gov); phone: 703-347-8044
I. FUNDING OPPORTUNITY DESCRIPTION
A. Introduction
Understanding the potential health risks posed by chemical substances in the environment is a major challenge elevated by the large number of diverse chemical substances with generally uncharacterized exposures, mechanisms, and toxicities. Tens of thousands of chemicals are currently in use and hundreds more are introduced every year. Many of these chemical substances, including nanomaterials, have not been thoroughly evaluated for potential risks to human health and the environment. A national research priority in the EPA’s Office of Research and Development (ORD) is Chemical Safety for Sustainability (CSS). Moving toward a safer and more sustainable environment requires new information and methods to make better-informed, more-timely decisions about chemicals. This requires innovative toxicity testing methods and new prediction techniques in computational toxicology that integrate multiple fields of science and technology to better understand the basis of lifestage-specific susceptibilities. EPA currently supports a number of computational toxicology-related research grants resulting from previous solicitations. Information regarding current research can be found on ORD’s National Center for Environmental Research (NCER) web site at Computational Toxicology.
EPA’s CSS Research Program is investigating new ways to address several longstanding difficulties with managing the safety of chemical substances, particularly in assessing their potential risk to human health and the environment. For example, there are over 80,000 chemicals in the Toxic Substance Control Act (TSCA) Inventory, yet only a small number have extensive toxicity testing information. Traditional chemical toxicity testing is expensive, time consuming and uses a significant number of animals. Although not perfect, the current model systems for predicting toxicity, classifying environmental hazards, and evaluating dose-response have been the gold standard for many years. A new testing paradigm was recommended by the National Research Council for the 21st Century in which the traditional methods would be enhanced or replaced with cell-based in vitro approaches that inform targeted-testing with in vivo models. A research goal of EPA is to support the development of tools to rapidly screen and evaluate large numbers of chemicals in manners that become less reliant on whole animal tests and will rely instead on systems-oriented, computational models. These data and models would help elucidate pathways that proceed from an initiating molecular event in which a chemical interacts with a biological target(s); continue on through a sequential series of key events embedded in biological processes; and ultimately culminate in an adverse outcome to humans or ecological species.
This solicitation is seeking applications proposing to lead investigations on three-dimensional in vitro models, hereafter referred to as ‘organotypic culture models’ (OCMs), that can discern toxic effects of chemical substances. Tissues and organs are three dimensional (3D) and function in a 3D milieu. Toxicological studies have been relying primarily on two-dimensional (2D) cell culture and animal model systems. However, cells grown on rigid 2D substrata can differ from in vivo systems in most aspects of cellular function, including morphology, proliferation, differentiation and communication within and between cells. OCMs have the advantage of being amenable to rapid experimental manipulations and imaging techniques, often difficult or impractical using whole-animal systems. OCMs using living cells that mimic structural and physiological features of animal tissues thus bridge the gap between conventional monolayer cell cultures and in vivo models. The development and evaluation of foreseen OCMs should accelerate translational research in computational toxicology. For applications using human cells, it is preferred that the cells are already available or derive from available cell lines. Under EPA Regulation 40 CFR Part 26 (Protection of Human Subjects), using pre-existing human cell lines is not considered human subjects research.
This solicitation provides the opportunity for the submission of applications for projects that may involve human subjects research. Human subjects research supported by the EPA is governed by EPA Regulation 40 CFR Part 26 (Protection of Human Subjects). This includes the Common Rule at subpart A and prohibitions and additional protections for pregnant women and fetuses, nursing women, and children at subparts B, C, and D. Research meeting the regulatory definition of intentional exposure research found in subpart B is prohibited by that subpart in pregnant women, nursing women, and children. Research meeting the regulatory definition of observational research found in subparts C and D is subject to the additional protections found in those subparts for pregnant women and fetuses (subpart C) and children (subpart D). All applications must include a Human Subjects Research Statement (HSRS, as described in Section IV.B.8), and if the project involves human subjects research, it will be subject to an additional level of review prior to funding decisions being made as described in Sections V.C and V.D of this solicitation.
Guidance and training for investigators conducting EPA-funded research involving human subjects may be obtained here:
Ethics, Regulations, and Policies
Human Subjects Research at the Environmental Protection Agency: Ethical Standards and Regulatory Requirements
B. Background
Technological and scientific advances in cell and molecular biology, chemistry and toxicology, computer science and systems modeling are leading to new ways to more effectively and efficiently rank chemicals based on their in vitro biological activity and potential exposure. The objective of the research Center(s) to be supported under this RFA is to further the development and evaluation of OCMs that will help accelerate translational research in predictive toxicology. It is expected that these OCMs will provide data at a higher level of biological organization not currently captured with cell-molecular based assays. OCMs that capture the complex 3D physiology of an in vivo tissue or organ are expected to provide tools, models, and data on critical linkages between molecular targets and tissue-level alterations. Research Centers responsive to this solicitation will develop and/or evaluate OCMs that: (1) recapitulate in vitro the sequential steps leading to AOPs for in vivo endpoints relevant to environmental health protection (e.g., development, reproduction, cancer); (2) are amenable to higher throughput formats because of the need to test a large number of chemicals and their break-down products that may be environmental contaminants; and (3) are amenable to quantitative multiplexed and multi-resolution assays (e.g., high content imaging, genomic approaches) in routine assay formats. Specific areas of interest include OCMs that can be used to test for the effects of chemicals on biological pathways and cellular dynamics relevant to development, reproduction, endocrine disruption, and cancer, and that could provide quantitative information to predict dose-response. Examples of specific areas of interest include, but are not limited to, cell-cell signaling pathways (e.g., Wnt, Shh, Delta-Notch, TGF-beta, Receptor Tyrosine Kinases, and retinoic acid receptors) and endocrine pathways (e.g., estrogen, thyroid, adrenal, and hypothalamic-pituitary) and their associated target tissues. Emphasis should be placed on assays with the capability to be run in a reproducible, medium or high-throughput manner.
OCMs may make use of tissues harvested in vivo (e.g., embryonic tissue) to follow morphogenesis and differentiation, e.g., brain-slices to follow synaptic development in a particular region of the nervous system (e.g., hippocampus), or stabilizing metabolic competency in liver. For longer-term evaluation, 3D models may be established starting from cells isolated from tissues, cell lines or stem cells. Reciprocal stromal-epithelial interactions are key events in AOPs for breast cancer that can be missed in a 2D culture system platform. Due to subtleties in cell shape and polarity, growth and malignant behavior of mammary epithelial cells can be regulated at the level of the tissue organization. Most cells have polarity and a directional function associated with that polarity. As such, OCMs likely need to maintain or include cellular polarity in order to approach normal function (e.g., apical and baso-lateral compartments). In some instances such polarity can be mechanical and in others can be the result of self-assembly or differentiation in culture where tight junctions form and tissue-like features emerge, cultivation of pluripotent stem cells on 3D scaffolds allows the generation of organ-like structures that resemble their in vivo counterparts when supported by appropriate micro-environmental cues.
Relatively little is known concerning the potential toxicological risks of the great majority of chemicals in commerce or in the environment because they have not been tested adequately. Testing of the safety of chemicals has relied heavily on contentious, resource-intensive in vivo testing. A challenge for human health and ecological toxicologists is the transparent application of mechanistic (e.g., molecular, biochemical, histological) data to risk assessments. Diverse in vitro screening assays are now being applied for testing of large numbers of chemical substances for biological activity and potential toxicity. Many significant findings in cell biology and toxicology have come from cultures of cells grown in monolayer; however, in vivo tissues and organ systems develop in 3 dimensions. Cells grown on flat, rigid 2D substrata can differ in their morphology, differentiation, and cell signaling versus those growing in a more physiological 3D environment. It has been shown that cells in 2D often have different patterns of gene expression as compared to those in 3D systems.
Several factors have motivated the development and evaluation of ‘Organotypic Culture Models’ (OCMs) for modeling cellular systems. One is the need for research models that capture complex cell-cell and cell-extracellular matrix (ECM) interactions and stabilize cell growth, organization and differentiation. In tissues, cells connect not only to each other but also to the ECM. This imparts distinct mechanical properties but also contributes to biochemical cues to the cellular environment via selective binding and release of growth factors, cytokines, morphogens, and other biologically active molecules. Receptors on the cell surface may determine how the cells interpret these cues. For example, ECM-mediated signal transduction events can lead to diverse changes in gene expression that influence the spatio-temporal fate of cells. Biochemical signals or responses that go awry due to genetic errors or chemical disruption in the system may have deleterious consequences on higher order tissue structure or function. These adverse outcome pathways (AOP) may lead to cancers, developmental defects, or disruptions in normal function. The adverse outcome pathway is a conceptual framework to portray causal and predictive linkages between molecular-cellular disruption (initiation of a toxicity or disease pathway) and adverse outcomes relevant to risk assessment and management. Subtleties in the complex mechanical and biochemical interplay underlying the coordinated regulation of these cellular activities are not easily captured in a conventional 2D assay format. Many studies have shown little correlation between the relative toxicity of nanoparticles following in vitro cellular and in vivo exposures[e.g., Sayes et. al. 2007]. Even co-cultures of alveolar epithelial cells and macrophages have not completely simulated the lung microenvironment with regard to surfactant interaction, particle clearance and recruitment of inflammatory cells in the lungs [Sayes et al, 2007].
Therefore, there is a growing demand for innovative 3D tissue mimetics that capture more of the relevant biology of the cellular micro-environment than traditional 2D cultures can possibly deliver. While 2D models can reveal important influences of the micro-environment on individual cellular behaviors (e.g., shape, cytoskeletal arrangement, chemotaxis and cell migration, differential growth and adhesion), it is the hierarchical arrangements and collective behavior of many interacting cells in a complex 3D architecture that drives the response of an integrated system. As such, OCMs may help to advance scientific understanding of the underlying pathophysiology and multicellular consequences that link molecular initiating events to key cell events in AOPs relevant to chemical risks.
Another motivation for the development of OCMs is the need for routine mid- to high-throughput assay formats that capture important facets of a physiological response to chemicals or their metabolites. While animal models may capture much of this complexity, they do not always predict toxicological effects in humans, nor facilitate an increased understanding of the mechanistic pathways and modes of action. OCMs based on human cells may capture the subtleties of a complex 3D tissue physiology to help identify molecular initiating events and establish mechanisms in screening of chemical substances for biological activity. As such, modeling cellular systems using in vitro 3D systems can help narrow the gap between animal models and human studies for toxicological effects of chemical substances.
A third motivation is the need to develop improved simulations of complex biological systems. To support chemical risk assessment paradigms that rely heavily on high throughput in vitro chemical screening data, in silico models of complex biological systems are needed to translate in vitro effects data into predicted in vivo outcomes, including relevant concentration-duration-response relationships. OCMs represent critical research tools that can be manipulated experimentally in a manner that allows paracrine regulation among closely associated cells and/or cell types to be differentiated from autocrine regulation within cells and endocrine regulation between tissues and organ systems within a whole organism. As such, they are positioned to provide unique insights into biological control mechanisms that can lead to more complex biological simulations that consider interactions of cells and cell types within a 3D milieu.
General Description of EPA Extramural Research Center
A Research Center, as intended in this RFA, entails multidisciplinary, thematic approaches to research needs on a much broader scale than individual projects. A Center allows for flexibility in examining not just the most recent science, but the full complement of considerations that may impact an issue, e.g., social or technical, as they develop. In promoting integrated, trans-disciplinary research, EPA seeks applications that demonstrate that the research team has worked together to design the proposed program, ensure that the Center reflects the input and interactions of different disciplines within the team, and that the Center as a whole reflects the collective thinking of a multidisciplinary team. It is not sufficient to list a collection of insular projects even if they address complementary topics. EPA recognizes that tight scientific integration can be a challenge, but this is a high priority for the Agency. Applicants are expected to: demonstrate how the various activities and projects contained within their proposals are integrated; encourage participation of investigators with the needed expertise and qualifications; employ cutting-edge technologies and approaches; and engage eligible stakeholders and partners who can help the Center achieve the goals of this RFA. This RFA presents the opportunity for investigators from different disciplines and organizations to work together on larger problems than can be addressed in a single grant proposal. Applicants are expected to propose projects (a maximum of five) within the Center that collectively adequately address the research needs described in this RFA.
In order to stimulate state-of-the-art research results, partnerships and collaborations are strongly encouraged and will be evaluated as part of the peer review evaluation under Section V. Please refer to Contracts and Subawards if your organization intends to identify a collaborator, including an independent third party evaluator in your proposal, and intend to use EPA funds to compensate them.
The specific Strategic Goal and Objective from the EPA’s Strategic Plan that relate to this solicitation are:
Goal 4: Ensuring the Safety of Chemicals and Preventing Pollution, Objective 4.1: Ensure Chemical Safety,
More information can be found in EPA’s FY 2011-2015 Strategic Plan
C. Authority and Regulations
The authority for this RFA and resulting awards is contained in the Toxic Substances Control Act, Section 10, 15 U.S.C. 2609, and the Federal Insecticide, Fungicide, and Rodenticide Act, Section 20, 7 U.S.C. 136r.
For research with an international aspect, the above statutes are supplemented, as appropriate, by the National Environmental Policy Act, Section 102(2)(F).
Note that a project’s focus is to consist of activities within the statutory terms of EPA’s financial assistance authorities; specifically, the statute(s) listed above. Generally, a project must address the causes, effects, extent, prevention, reduction, and elimination of air pollution, water pollution, solid/hazardous waste pollution, toxic substances control, or pesticide control depending on which statute(s) is listed above. These activities should relate to the gathering or transferring of information or advancing the state of knowledge. Proposals should emphasize this “learning” concept, as opposed to “fixing” an environmental problem via a well-established method. Proposals relating to other topics which are sometimes included within the term “environment” such as recreation, conservation, restoration, protection of wildlife habitats, etc., must describe the relationship of these topics to the statutorily required purpose of pollution prevention and/or control.
Applicable regulations include: 40 CFR Part 30 (Uniform Administrative Requirements for Grants and Agreements with Institutions of Higher Education, Hospitals, and Other Non-Profit Organizations), 40 CFR Part 31 (Uniform Administrative Requirements for Grants and Cooperative Agreements to State and Local Governments) and 40 CFR Part 40 (Research and Demonstration Grants). Applicable OMB Circulars include: OMB Circular A-21 (Cost Principles for Educational Institutions) relocated to 2 CFR Part 220, OMB Circular A-87 (Cost Principles for State, Local and Indian Tribal Governments) relocated to 2 CFR Part 225, and OMB Circular A-122 (Cost Principles for Non-Profit Organizations) relocated to 2 CFR Part 230.
D. Specific Research Areas of Interest/Expected Outputs and Outcomes
Note to applicant: The term “output” means an environmental activity or effort, and associated work products, related to a specific environmental goal(s), (e.g., testing a new methodology), that will be produced or developed over a period of time under the agreement. The term “outcome” means the result, effect, or consequence that will occur from the above activit(ies) that is related to an environmental or health-related objective.
The goals of this RFA are to support Centers for research and development of Organotypic Culture Models (OCMs) that:
- Capture complex cell-cell and cell-extracellular matrix interactions;
- Provide innovative 3D tissue mimetics or microphysiological systems;
- Advance the understanding of the underlying pathophysiology and multicellular consequences linking molecular initiating events to AOPs relevant to chemical risks;
- Lead to mid- to high-throughput assays capturing physiological responses to chemicals or their metabolites;
- Simulate complex biological systems’ response to chemical substances.
The overall Center proposal will be evaluated for its cohesive integration of individual Research Projects to comprehensively address the following research questions:
- What approach will be utilized to develop organotypic cell models that recapitulate specific aspects of normal physiology, and what techniques will be used to characterize the in vitro model system in comparison to the in vivo counterpart? EPA is particularly interested in systems that include characterization of the molecular and cellular pathways perturbed by environmental chemicals.
- How will Adverse Outcome Pathways (AOP) based models be developed that allow for quantitative measurement of linkages between molecular initiating events and relevant adverse outcomes, including key events that require the dynamics of a 3D culture? How will your OCMs be employed to establish linkages between molecular initiating events and adverse outcomes relevant to risk assessment and environmental management decisions (i.e., disease or dysfunction in humans, impacts on survival, growth, and/or reproduction in non-human organisms), and what metrics will be used to establish their certainty?
- What steps will be taken towards developing and implementing approaches and techniques to characterize the dosimetry of a chemical substance, including nanomaterials, as they relate to pathway perturbation, both as a function of stressor severity (e.g., dose) and duration or timing of the perturbation?
- By what innovations will proposed OCMs be made amenable to medium or high throughput screening assays?
Proposals should focus on collaborative efforts towards state-of-the-art assay development and data generation. The use of innovative research approaches is encouraged. For example, areas that are not currently covered by OCMs would be ideal for new assay development, or ‘organ-on-a-chip’ microdevices fabricated to enable microfluidics for oxygenation and transport into the underlying microvascular channels. Areas of pursuit may include characterization of relative risk from specific chemicals or chemical classes, or characterization of susceptibility associated with risks from lifestage-specific exposure to chemicals. Refer to the following web link for list of chemicals of potential interest based on EPA’s computational toxicology research program ToxCast™ Chemicals. The ToxCast library of compounds will be made available for screening in the proposed OCMs.
Outputs from the proposed Center may include:
- Innovative advanced cell culture techniques that can recapitulate organ system structures and exhibit finely differentiated responses to environmental exposures.
- Complex cell or tissue culture models which can characterize the physical and chemical properties that influence pharmacokinetics, bioavailability, and bioactivity of adverse biological effects of chemicals toxicity specific to organ systems.
- Description of biomarkers which can link key dynamic cellular changes resulting from chemical exposure to organ system or higher level in vivo effects.
- Refined characterization of the complex relationship between specific environmental chemical stressor exposure, internal dose, and adverse outcomes.
Products expected from the research funded under this RFA are expected to support multi-scale computational modeling and simulation efforts that make use of the data generated to investigate chemical effects on complex cellular interactions and extrapolation to tissue-level consequences in vivo. Outputs may include data, tools and approaches that address fundamental processes underlying higher-order alterations (e.g., disruption of cellular morphogenesis or differentiation leading to adverse developmental outcomes; endocrine-disruptive pathways leading to adverse reproductive outcomes). Of particular interest are outputs that can be used to capture information on molecular initiating events and key cellular events that reconstruct AOPs relevant to toxicological endpoints.
Outcomes from the proposed Center may include:
- Better identification of key connections in the continuum between the production of chemical substances and adverse outcomes in humans so that sustainable approaches can be scaled up for risk management purposes.
- More reliable identification and delineation of toxicity pathways from biologic interactions at target tissues or early cellular changes that lead to cell injury and systemic perturbations.
- Transformation of chemical toxicity testing that takes advantage of advances in biology and computer modeling to reduce reliance on whole animal toxicity testing while at the same time providing for more efficient and cost-effective methods for characterizing hazards (or lack thereof) associated with the thousands of environmental chemicals lacking toxicity data.
- Implementation of quantitative risk assessment techniques that reduce uncertainties in extrapolation from in vitro systems to in vivo outcomes.
- Improved understanding of the control of complex biological systems through autocrine, paracrine, and endocrine modes of regulation.
Results of the research are expected to provide: (1) a better understanding of the mechanisms by which cell-level effects may propagate into tissue-level consequences; (2) new hypotheses to formally guide novel experiments aiming to qualify OCM performance; (3) complex models for linking molecular pathways and to complex arrangements of cells and ultimately to distinct AOPs; and (4) better ways to assess the impacts of exposure to chemicals at various life-stages and scales of biological organization.
To the extent practicable, research proposals must embody innovation. Innovation, for the purposes of this RFA, is defined as the process of making changes; a new method, custom or device. Innovative research can take the form of wholly new applications or applications that build on existing knowledge and approaches for new uses. Research proposals must include a discussion on how the proposed research is innovative (see Section IV.B.6). ORD will draw from the above-mentioned innovation definition in the review/evaluation process of recommending research proposals (see Section V.A).
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- Griffith, L.G., and Swartz, M.A. Capturing complex 3D tissue physiology in vitro. Nature Rev 7: 211-224 (2006).
- Yamada, K.M., and Cukierman, E. Modeling tissue morphogenesis and cancer in 3D. Cell 130: 601-610 (2007).
- Inglese, J., Johnson, R.L., Simeonov, A., Xia, M., Zheng, W., Austin, C.P., Auld D.S. High-throughput screening assays for the identification of chemical probes. Nature Chem Biol 3: 466-479 (2007).
- Judson, R.S., Houck, K.A., Kavlock, R.J., Knudsen, T.B., Martin, M.T., Mortensen, H.M., Reif, D.M., Rotroff, D.M., Shah, I., Richard, A.M., and Dix, D.J. In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project. Environ Health Persp 118: 485-492 (2010).
- National Research Council. Toxicity Testing in the 21st Century, A Vision and a Strategy. The National Academies Press, Washington, DC (2007).
- Ankley, G.T., Bennett, R.S., Erickson, R.J., Hoff, D.J., Hornung, M.W., Johnson, R.D., Mount, D.R., Nichols, J.W., Russom, C.L., Schmieder, P.K., Serrrano, J.A., Tietge, J.E., and Villeneuve, D.L. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29: 730-741(2010).
- Abbott, B.D., and Birnbaum, L.S. TCDD exposure of human embryonic palatal shelves in organ culture alters the differentiation of medial epithelial cells. Teratology 43: 119-132 (1991).
- Huang, C., and Hales, B.F. Teratogen responsive signaling pathways in organogenesis stage mouse limbs. Reprod Toxicol. 27: 103-110 (2009).
- Stoppini, L., Buchs, P.A., and Muller, D. A simple method for organotypic cultures of nervous tissue. J Neuro Meth 37: 173-182 (1991).
- Kim, Y., and Rajagopalan, P. 3D Hepatic Cultures Simultaneously Maintain Primary Hepatocyte and Liver Sinusoidal Endothelial Cell Phenotypes. PLoS ONE 5(11): e15456 (2010).
- Weaver, V.M., Petersen, O.W., Wang, F., Larabell, C.A., Briand, P., Damsky, C., and Bissell, M.L. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 137: 231–245 (1997).
- Krause, S., Maffini, M.V., Soto, A.M., and Sonnenschein, C. The microenvironment determines the breast cancer cells' phenotype: organization of MCF7 cells in 3D cultures. BMC Cancer 10: 263 (2010).
- van de Kamp, J., Kramann, R., Anraths, J., Schöler, H.R., Ko, K., Knüchel, R., Zenke, M., Neuss, S., and Schneider, R.K. Epithelial morphogenesis of germline-derived pluripotent stem cells on organotypic skin equivalents in vitro. Differentiation 83: 138-147.
- Domansky, K., Inman, W., Serdy, J., Dash, A., Lim, M.H., and Griffith, L.G. Perfused multiwell plate for 3D liver tissue engineering. Lap Chip 10: 51-58 (2010).
- Huh, D., Matthews, B.D., Mammoto, A., Montoya-Zavala, M., Hsin, H.Y., and Ingber, D.E. Reconstituting organ-level lung functions on a chip. Science 328: 1662-1668 (2010).
- Knudsen, T.B., and Kleinstreuer, N.C. Disruption of embryonic vascular development in predictive toxicology. Birth Defects Res C 93: 312-323 (2012).
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- Sayes CM, Reed KL, Warheit DB. Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 2007, 97: 163-180.
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F. Special Requirements
Agency policy and ethical considerations prevent EPA technical staff and managers from providing applicants with information that may create an unfair competitive advantage. Consequently, EPA employees will not review, comment, advise, and/or provide technical assistance to applicants preparing applications in response to EPA RFAs. EPA employees cannot endorse any particular application.
Multiple Investigator applications may be submitted as: (1) a single Lead Principal Investigator (PI) application with Co-PI(s) or (2) a Multiple PI application (with a single Contact PI). Multiple PI applications must follow the specific instructions provided in Sections IV. and V. of this RFA. For further information, please see the EPA Implementation Plan for Policy on Multiple Principal Investigators (Research Business Models Working Group).
Groups of two or more eligible applicants may choose to form a Center and submit a single application for this assistance agreement. Applications must identify which organization will be the recipient of the assistance agreement and which organizations(s) will be subawardees of the recipient. Partnerships and collaborations are strongly encouraged and will be evaluated as part of the peer review evaluation under Section V. For applicants proposing a subgrant(s) in the application, please see Section IV.B.12 of this solicitation for budget information and refer to Contracts and Subawards.
This solicitation provides the opportunity for the submission of applications for projects that may involve human subjects research. There are many scientific and ethical considerations that must be addressed in such studies by the study sponsor and research team, including, but not limited to, those related to recruitment, retention, participant compensation, third-party issues, researcher-participant interactions, researcher-community interactions, communications, interventions, and education. All such research must comply with the requirements of 40 CFR Part 26, and any human observational exposure studies must also adhere to the principles set forth in the Scientific and Ethical Approaches for Observational Exposure Studies (SEAOES) (EPA/600/R-08/062) (PDF) (133 pp, 1.21 MB) document. SEAOES, which was published by researchers in EPA and which discusses the principles for the ethical conduct of human research studies, serves as a resource for applicants interested in applying under this solicitation. References to “SEAOES Principles” in this solicitation refers, in general, to the issues of interest in conducting human subjects research studies that maintain the highest scientific and ethical standards and safety during the conduct of these studies. All applications must include a Human Subjects Research Statement (HSRS; described in Section IV.B.8) and if the project involves human subjects research, it will be subject to an additional level of review prior to funding decisions being made as described in Sections V.C and V.D of this solicitation. Under EPA Regulation 40 CFR Part 26 (Protection of Human Subjects) covering the Common Rule, human cell lines are not covered in the definition of human subjects.
The application shall include a plan (see “Data Plan” in section IV.B.9) to make available to the NCER project officer all data generated (first produced under the award) from observations, analyses, or model development used under an agreement awarded from this RFA. The data must be available in a format and with documentation such that they may be used by others in the scientific community.
As described more fully in Section IV, each application should address the following items (for content and form of application submission and page limitations, see Section IV.B).
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Center Description (5-page limit): Applications should describe the overall goals, objectives, and approach for the Center, including how the Center will pursue multidisciplinary, comprehensive, and thematic research. The Center description should demonstrate how the various projects contained within the Center are integrated. The qualities of Research Projects should complement each other and reflect the Center’s overall approach. The Center description must describe the expertise and qualifications of participating investigators and discuss the complementary support provided by each member and partner.
The application should describe how the Center’s work will produce complex cell or tissue culture models which can characterize the physical and chemical properties that influence pharmacokinetics, bioavailability, and bioactivity of adverse biological effects of chemicals toxicity specific to organ systems. The proposed efforts should seek innovative solutions that identify key connections in the continuum between the production of chemical substances and adverse outcomes in humans. The application should also describe the Center’s commitment to transforming chemical toxicity testing that takes advantage of advances in biology and computer modeling.
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Research Project Descriptions (15-page limit for each project description): Applications should contain a maximum of five projects that address the research questions described above in Section I.D. Each of the specific individual research projects should be completely described according to the instructions in Section IV below. Individual project descriptions should explain how the project fits into the overall Center’s program and relates to other projects in the application.
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Administrative Unit Description (15-page limit): The Center shall have an Administrative Unit which provides oversight, coordination and integration of the Center’s activities. Describe how the Administrative Unit will coordinate the research activities and how the program will be integrated internally. Center proposals should take a multidisciplinary approach and indicate how programmatic and funding decisions will be made; how project objectives will be successfully achieved in a timely manner in accordance with project schedules and milestones; how investigators from different disciplines within the Center will communicate on a regular basis about the development and progress of Center projects; how progress toward achieving the expected results (outputs and outcomes) will be monitored and measured; who will set priorities and who will ensure the quality of the research. The approach, procedures, and controls for ensuring that awarded grant funds will be expended in a timely and efficient manner should also be described. In conducting its research, the Center should apply measures of success or progress, including developing and promoting the use of statistically valid protocols to evaluate program effectiveness and applying metrics to evaluate the project’s success, progress, or effectiveness.
It is anticipated that a total of approximately $18 million will be awarded under this announcement, depending on the availability of funds, quality of applications received, and other applicable considerations. The EPA anticipates funding approximately 3 awards under this RFA. Requests for amounts in excess of a total of $6,000,000, including direct and indirect costs, will not be considered. The total project period requested in an application submitted for this RFA may not exceed 4 years.
The EPA reserves the right to reject all applications and make no awards, or make fewer awards than anticipated, under this RFA. The EPA reserves the right to make additional awards under this announcement, consistent with Agency policy, if additional funding becomes available after the original selections are made. Any additional selections for awards will be made no later than six months after the original selection decisions.
In appropriate circumstances, EPA reserves the right to partially fund proposals/applications by funding discrete portions or phases of proposed projects. If EPA decides to partially fund a proposal/application, it will do so in a manner that does not prejudice any applicants or affect the basis upon which the proposal/application, or portion thereof, was evaluated and selected for award, and therefore maintains the integrity of the competition and selection process.
EPA may award both grants and cooperative agreements under this announcement.
Under a grant, EPA scientists and engineers are not permitted to be substantially involved in the execution of the research. However, EPA encourages interaction between its own laboratory scientists and grant Principal Investigators after the award of an EPA grant for the sole purpose of exchanging information in research areas of common interest that may add value to their respective research activities. This interaction must be incidental to achieving the goals of the research under a grant. Interaction that is “incidental” does not involve resource commitments.
Where appropriate, based on consideration of the nature of the proposed project relative to the EPA’s intramural research program and available resources, the EPA may award cooperative agreements under this announcement. When addressing a research question/problem of common interest, collaborations between EPA scientists and the institution’s principal investigators are permitted under a cooperative agreement. These collaborations may include data and information exchange, providing technical input to experimental design and theoretical development, coordinating extramural research with in-house activities, the refinement of valuation endpoints, and joint authorship of journal articles on these activities. Proposals may not identify EPA cooperators or interactions; specific interactions between EPA’s investigators and those of the prospective recipient for cooperative agreements will be negotiated at the time of award.
A. Eligible Applicants
Public nonprofit institutions/organizations (includes public institutions of higher education and hospitals) and private nonprofit institutions/organizations (includes private institutions of higher education and hospitals) located in the U.S., state and local governments, Federally Recognized Indian Tribal Governments, and U.S. territories or possessions are eligible to apply. Profit-making firms are not eligible to receive assistance agreements from the EPA under this program.
Eligible nonprofit organizations include any organizations that meet the definition of nonprofit in OMB Circular A-122, located at 2 CFR Part 230. However, nonprofit organizations described in Section 501(c) (4) of the Internal Revenue Code that lobby are not eligible to apply.
Foreign governments, international organizations, and non-governmental international organizations/institutions are not eligible to apply.
National laboratories funded by Federal Agencies (Federally-Funded Research and Development Centers, “FFRDCs”) may not apply. FFRDC employees may cooperate or collaborate with eligible applicants within the limits imposed by applicable legislation and regulations. They may participate in planning, conducting, and analyzing the research directed by the applicant, but may not direct projects on behalf of the applicant organization. The institution, organization, or governance receiving the award may provide funds through its assistance agreement from the EPA to an FFRDC for research personnel, supplies, equipment, and other expenses directly related to the research. However, salaries for permanent FFRDC employees may not be provided through this mechanism.
Federal Agencies may not apply. Federal employees are not eligible to serve in a principal leadership role on an assistance agreement, and may not receive salaries or augment their Agency’s appropriations in other ways through awards made under this program.
The applicant institution may enter into an agreement with a Federal Agency to purchase or utilize unique supplies or services unavailable in the private sector to the extent authorized by law. Examples are purchase of satellite data, chemical reference standards, analyses, or use of instrumentation or other facilities not available elsewhere. A written justification for federal involvement must be included in the application. In addition, an appropriate form of assurance that documents the commitment, such as a letter of intent from the Federal Agency involved, should be included.
Potential applicants who are uncertain of their eligibility should contact Ron Josephson (josephson.ron@epa.gov) in NCER, phone: 703-308-0442.
B. Cost-Sharing
Institutional cost-sharing is not required.
C. Other
Applications must substantially comply with the application submission instructions and requirements set forth in Section IV of this announcement or they will be rejected. In addition, where a page limitation is expressed in Section IV with respect to parts of the application, pages in excess of the page limit will not be reviewed. Applications must be submitted through grants.gov or by other authorized alternate means (see Section IV.E. “Submission Instructions and Other Submission Requirements” for further information) on or before the solicitation closing date and time in Section IV of this announcement or they will be returned to the sender without further consideration. Also, applications exceeding the funding limits or project period term described herein will be returned without review. Further, applications that fail to demonstrate a public purpose of support or stimulation (e.g., by proposing research which primarily benefits a Federal program or provides a service for a Federal agency) will not be funded.
Applications which include more than five research projects will be deemed ineligible.
Applications deemed ineligible for funding consideration will be notified within fifteen calendar days of the ineligibility determination.
IV. APPLICATION AND SUBMISSION INFORMATION
Additional provisions that apply to this solicitation and/or awards made under this solicitation, including but not limited to those related to confidential business information, contracts and subawards under grants, and proposal assistance and communications, can be found at Fiscal Year 2010 Competitive Grant Awards
These, and the other provisions that can be found at the website link, are important, and applicants must review them when preparing applications for this solicitation. If you are unable to access these provisions electronically at the website above, please communicate with the EPA contact listed in this solicitation to obtain the provisions.
Formal instructions for submission through Grants.gov follow in Section E.
A. Internet Address to Request Application Package
Use the application package available at Grants.gov (see Section E. “Submission Instructions and Other Submission Requirements”). Note: With the exception of the current and pending support form (available at Forms and Standard Instructions Download Page), all necessary forms are included in the electronic application package.
An email will be sent by NCER to the Lead/Contact PI and the Administrative Contact (see below) to acknowledge receipt of the application and transmit other important information. The email will be sent from receipt.application@epa.gov; emails to this address will not be accepted. If you do not receive an email acknowledgment within 30 days of the submission closing date, immediately inform the Eligibility Contact shown in this solicitation. Failure to do so may result in your application not being reviewed. See Section E. “Submission Instructions and Other Submission Requirements” for additional information regarding the application receipt acknowledgment.
B. Content and Form of Application Submission
The application is made by submitting the materials described below. Applications must contain all information requested and be submitted in the formats described.
Summary of Page and other Limitations for Application Content:
Descriptions must be single-spaced on 8.5x11-inch pages, with standard 12-point type and 1-inch margins. While these guidelines establish the minimum type size requirements, applicants are advised that readability is of paramount importance and should take precedence in selection of an appropriate font for use in the proposal.
The following page limitations may not be exceeded (excess pages will not be reviewed):
- Abstracts: 1-page abstract for the Center as a whole; 1-page abstracts for each proposed research project (no more than 5 project proposals are to be submitted)
- Center Description: 5 pages
- Research Plan(s): 15 pages for each research project description (no more than 5 project proposals are to be submitted)
- Quality Management Plan: 5 pages
- Human Subjects Research Statement: 6 pages
- Data Plan: 2 pages
- Administrative Unit: 15 pages
- Budget Justification: 2 pages per research project; 2 pages for the Admi
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.