and Human Services (HHS)
EXPIRED
Participating Organization(s) |
National Institutes of Health (NIH) |
National Institute of Environmental Health Sciences (NIEHS) |
|
Funding Opportunity Title |
Identification of Biomarkers for Early Detection of Environmentally-Induced Mitochondrial Dysfunction (R01) |
Activity Code |
R01 Research Project Grant |
Announcement Type |
New |
Related Notices |
None |
Funding Opportunity Announcement (FOA) Number |
RFA-ES-11-007 |
Companion FOA |
NoneNone |
Catalog of Federal Domestics Assistance (CFDA)
Number(s) |
93.113 |
FOA Purpose |
This funding opportunity announcement (FOA) encourages grant applications from institutions/organizations to develop biomarkers of mitochondrial dysfunction using animal models and other experimental models that can help to identify environmental stressors that inhibit normal mitochondrial function, improve our mechanistic understanding of the effects of mitochondrial toxicants, and develop approaches and candidate markers that will serve as the basis for developing biomarkers of early mitochondrial dysfunction in human population studies linking exposure to disease. Mitochondrial biology is complex, with different responses to stressors, diet composition, and genetic factors observed in different tissues and at different stages of development. Before early biomarkers of mitochondrial dysfunction can be fully developed for human studies, a number of important issues need to be addressed, including enhancing the understanding of how the more severe effects on mitochondrial function in target tissues relate to milder effects in surrogate tissues, understanding whether alterations in mitochondrial endpoints are adaptive or adverse (transient or persistent) effects, and determining which endpoints signal early effects on mitochondrial function before more severe tissue phenotypes are apparent. Many of these questions can be addressed through development of relevant animal and other experimental models to identify robust markers of mitochondrial dysfunction associated with genetic and environmental factors. |
Posted Date |
November 30, 2010 |
Open Date (Earliest Submission Date) |
January 3, 2011 |
Letter of Intent Due Date |
January 4, 2011 |
Application Due Date(s) |
February 3, 2011, by 5:00 PM local time of applicant organization. |
AIDS Application Due Date(s) |
Not applicable |
Scientific Merit Review |
May 2011 |
Advisory Council Review |
August 2011 |
Earliest Start Date(s) |
September 2011 |
Expiration Date |
February 4, 2011 |
Due Dates for E.O. 12372 |
Not Applicable |
Required Application Instructions
It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission
Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
Mitochondrial dysfunction is associated with numerous chronic diseases including Type II diabetes, metabolic syndrome, neurodegenerative diseases, blindness, cardiovascular disease, and cancer. Although it is known that mitochondria are a target for numerous environmental compounds, including pesticides, bacterial and fungal toxins, and multiple industrial chemicals, there are only a few well-studied links between disease and mitochondrial dysfunction resulting from environmental exposures. Research in this area is hampered by a lack of tools to measure early markers of mitochondrial dysfunction in human studies, particularly with respect to ambient environmental exposures. Current clinical markers for mitochondrial dysfunction typically detect only advanced symptoms of tissue injury and disease. There is an urgent need for reliable, informative markers of early mitochondrial dysfunction associated with environmental stressors, as these will enhance the mechanistic understanding of environmentally-induced mitochondrial toxicity and disease and enable prevention and intervention in the subclinical stages of disease.
In addition to their central role in cellular bioenergetics, mitochondria also play a major role in apoptosis, control of cytosolic calcium concentrations, and metabolic cell signaling. Through normal energy production by oxidative phosphorylation and ATP generation via the electron transport chain, mitochondria proteins and mtDNA are vulnerable to damage from reactive oxygen species (ROS). Mitochondria are also susceptible to damage from numerous natural and synthetic compounds that exert their toxicity by affecting the integrity of mtDNA, inhibiting complexes in the electron transport chain, altering membrane potential, affecting calcium homeostasis, and by modulating induction of apoptosis. Mitochondrial dysfunction is associated with numerous chronic diseases, and may reflect, in part, the vulnerability of mitochondria to environmental influences. For example, the pesticide rotenone is a potent Complex I inhibitor, exhibits selective toxicity for dopaminergic neurons, and is associated in human studies with increased risk of Parkinson’s disease (PD).
The identification of mitochondrial impairment in clinical settings is challenging. Acute exposure to mitochondrial toxicants causes short-term and nonspecific clinical symptoms that include muscle weakness, fatigue, hypotension and shortness of breath. Current clinical markers used to identify mitochondrial dysfunction in diseases include measurement of serum lactate, histological and genetic markers from muscle biopsies, and some imaging technologies. These markers are typically detected in patients with advanced symptoms of mitochondrial dysfunction and therefore have limited application to large-scale population studies to detect mitochondrial dysfunction at a stage where intervention is possible. There is a need for biomarkers of early mitochondrial dysfunction associated with environmental exposures. For application to large-scale population studies, biomarkers of mitochondrial dysfunction will need to be developed in easily accessible tissues, including blood, buccal mucosa, and urine. However, mitochondrial biology varies between tissues and at different stages of development. Before biomarkers can be fully developed for human studies, a number of research questions need to be addressed including: Why are some tissues or cell types more susceptible to mitochondrial dysfunction from environmental exposures or genetic mutations? Why do certain mitochondrial diseases show such tissue specificity? Are there less severe systemic effects that are detectable in surrogate tissue? How do protein, metabolite or other biochemical markers differ by cell type? How do changes in diet, activity, temperature, or genetic background affect the ability to detect effects of environmental stressors on mitochondrial function?
NIEHS sponsored a workshop on June 25, 2009, in conjunction with the United Mitochondrial Disease Foundation annual meeting held in Tyson s Corner, Virginia, to explore the state of the science and technology with experts in the field of mitochondrial physiology and function with the goal of developing recommendations on how to advance the field by developing improved biomarkers of mitochondrial dysfunction related to genetics and environmental exposures (Shaughnessy et al. Mitochondrion 2010 10(5):579-81). Workshop participants recommended support for the development of new and improved animal models and other experimental models to better understand tissue-specific effects of mitochondrial toxicants and to enhance the mechanistic understanding needed to develop assays in less-invasive biospecimens that reflect mitochondrial alterations in target tissues.
The goal of this program is to employ animal models and other experimental models to 1) identify mitochondrial targets of environmental stressors that indicate disruption of normal mitochondrial function 2) improve our understanding of the tissue-specific effects of mitochondrial toxicants and compare measures of mitochondrial dysfunction between target and surrogate tissues 3) provide a more comprehensive mechanistic understanding of the role of genetics and environment on mitochondrial dysfunction through the use of transgenic and trans-mitochondrial models, 4) help to set standards for analysis of mitochondrial endpoints to determine the best or most widely accepted cellular or biological measures that signal mitochondrial dysfunction, and 5) develop approaches and candidate markers that will serve as the basis for developing early biomarkers of mitochondrial dysfunction in human population studies linking exposure to disease.
Approaches can include, but are not limited to:
Research proposals must include the evaluation of effects of at least one environmental stressor that can include but is not limited to pesticides, toxic metals, bacterial or fungal toxins, or industrial chemicals or other compounds that induce oxidative or inflammatory stress. Proposals should justify the relevance of model systems to humans, for example, by noting the homology of genes, proteins or biological pathways to humans.
Anticipated outcomes of this program will be the identification of a set of tools and biomarkers that can be further developed and adapted to large-scale human population studies. The goal of these studies is to provide a deeper, more mechanistic understanding of how environmental stressors induce mitochondrial dysfunction. Applications that propose only to screen multiple environmental compounds for effects on mitochondrial function will be deemed non-responsive to this FOA and will not be reviewed.
Funding Instrument |
Grant |
Application Types Allowed |
New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types. |
Funds Available and Anticipated Number of Awards |
NIEHS intends to commit an estimated $2.5 million in fiscal year 2011 to fund six to eight awards. |
Award Budget |
Application budgets are not limited, but need to reflect actual needs of the proposed project. |
Award Project Period |
Applicants may propose a project period up to 5 years. |
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
Higher Education Institutions:
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For profit Organizations
Governments
Other
Foreign (non-U.S.) components of U.S. Organizations are allowed.
Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.
All Program Directors/Principal Investigators (PD/PIs) must
also work with their institutional officials to register with the eRA Commons
or ensure their existing eRA Commons account is affiliated with the eRA Commons
account of the applicant organization.
All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least four (4) weeks prior to the application due date.
Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Project Director/Principal
Investigator (PD/PI) is invited to work with his/her organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple
Program Director/Principal Investigator Policy and submission details in the Senior/Key
Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.
Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
Descriptive title of proposed research
Name, address, and telephone number of the PD(s)/PI(s)
Names of other key personnel
Participating institutions
Number and title of this funding opportunity
The letter of intent should be sent to:
Leroy Worth, PHD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
PO BOX 12233, MD K3-03
Research Triangle Park, NC 27709-2233
Telephone: 919-541-0670
Email: [email protected]
The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for application submission. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Resource Sharing Plan
Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS) as provided in the SF424 (R&R) Application Guide, with the following modifications:
Appendix
Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide
Foreign (non-US) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the SF424 (R&R) Application Guide.
Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.
Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.
Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.
Important
reminders:
All PD/PIs must include their eRA Commons ID in the Credential
field of the Senior/Key Person Profile Component of the SF 424(R&R) Application
Package. Failure to register in the Commons and to include a valid PD/PI
Commons ID in the credential field will prevent the successful submission of an
electronic application to NIH.
The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.
See more
tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by NIEHS, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.
In order to expedite review, applicants are requested to notify NIEHS Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Significance
Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Investigator(s)
Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Innovation
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Approach
Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be
managed?
If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?
Environment
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
Additional Review Criteria
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.
Protections for Human Subjects
For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.
Inclusion of Women, Minorities, and Children
When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.
Vertebrate Animals
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Biohazards
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmissions
Not applicable.
Renewals
Not applicable.
Revisions
Not applicable.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.
Applications from Foreign Organizations
Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIEHS (assignments will be shown in the eRA Commons), in accordance with NIH peer review policy and procedures, using the stated review criteria.
As part of the scientific peer review, all applications:
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA . Following initial peer review, recommended applications will receive a second level of review by the National Advisory Environmental Health Sciences Council. The following will be considered in making funding decisions:
After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants Policy
Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to the DUNS,
CCR Registration, and Transparency Act requirements as noted on the Award
Conditions and Information for NIH Grants website.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Cooperative Agreement Terms and Conditions of Award
Not Applicable.
When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.
A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
Grants.gov
Customer Support (Questions regarding Grants.gov registration and
submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: [email protected]
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]
eRA Commons Help Desk(Questions regarding eRA Commons
registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]
Daniel Shaughnessy, PhD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-2506
Email: [email protected]
Leroy Worth. PhD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-0670
Email: [email protected]
Aaron Nicholas
Division of Extramural Research and Training
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-7823
Email: [email protected]
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
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