It is critical that applicants follow the Research (R) Instructions in the SF424 (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

This FOA invites clinical research applications to elucidate circadian-dependent mechanisms contributing to the pathophysiology of human obesity, diabetes-related metabolism, obesity-coupled risks for heart, lung, and blood disease, and the identification of novel therapies to improve circadian rhythm for primary or secondary prevention and management of obesity-associated disease risks. Mechanistic clinical studies to elucidate the relationship of circadian rhythm to causal pathways of disease are encouraged. Intervention studies to identify circadian-mediated mechanisms of obesity, diabetes-related metabolism, and obesity-coupled heart, lung, and blood pathophysiology may be proposed. Behavioral, physiological, pharmacological, molecular, and genomic studies aimed at elucidating the relationship between circadian-dependent mechanisms and disease are appropriate. Multidisciplinary, multiple investigator teams are strongly encouraged to realize the full potential for synergy between experts in heart, lung, blood, and metabolic disorders with circadian and sleep researchers. Studies of epidemiological risk and clinical trials to assess therapeutic efficacy, effectiveness, or implementation are outside the scope of this program.

Circadian rhythm misalignment resulting from irregular or insufficient sleep schedules, biologically inappropriate light exposure, and diet-associated zeitgebers poses an emerging risk to health in developing societies world-wide. In the U.S., 30-40% of adults and 40-70% of adolescents report symptoms of poor circadian and sleep health annually. Mounting evidence links irregular work schedules (shiftwork) to biologically inappropriate light exposure and eating schedules that increase the risk of obesity, diabetes, cardiovascular disease, and stroke. Shift work affects 20-30% of US adults and disproportionately burdens low socioeconomic status populations and minorities. An array of genetic polymorphisms in combination with environmental factors influence propensity for sleep schedule preferences and are associated with obesity and diabetes risk, altered glucose/insulin metabolism, and the effectiveness of weight loss interventions. Time of day for meal consumption influences weight gain and the ability to lose and regulate weight. Effects of circadian misalignment on glucose metabolism and markers of vascular, immune, and neuroendocrine function have been reported, but mechanisms coupling circadian rhythms to disease pathophysiology are not well understood.

Recent advances indicate that the fundamental chemistry of cellular metabolism (e.g., mitochondrial oxidation state, glucose metabolism, fatty acid oxidation, nutrient sensing) and pathophysiology (e.g., oxidative/endoplasmic reticulum stress, impaired insulin secretion, inflammation) is coupled to circadian genomics. The molecular circadian clock appears to serve as an energy sensor that responds to dietary nutrients, re-dox state, ATP availability, and the timing of nutrient intake. In turn, the clock drives 10-20% of gene expression in many metabolically active tissues such as cardiomyocytes, smooth muscle, vascular endothelium, pancreatic islets, hepatocytes, adipocytes, immune cells, and gut. Circadian dependent functions are well-positioned to serve an integrative role synchronizing cellular metabolism and systemic physiology related to obesity, diabetes, and heart, lung, and blood disease. Circadian dysfunction in animal models, either through behavioral or genetic alteration produces a wide range of metabolic and cardiopulmonary pathophysiology such as hyperlipidemia, atherogenesis, oxidative injury, and altered glucose metabolism.

This FOA invites applications for clinical research that will couple recent advances in understanding circadian mechanisms in physiological systems, cellular function, and the genome to the pathophysiology of human obesity, diabetes, and obesity-coupled heart, lung, and blood disorders. Human circadian rhythms are potentially modifiable (e.g., sleep-wake schedules, bright light exposure, timing of meals, pharmacologic intervention), presenting an immediate opportunity to identify potential therapeutic targets for improving the prevention and management of obesity, diabetes, and obesity-coupled heart, lung, and blood disease. This FOA supports behavioral, physiological, pharmacological, and molecular/genetic level strategies, with a mechanistic focus, to elucidate circadian-mediated pathophysiological mechanisms of human obesity, diabetes-related metabolism, and obesity-coupled heart, lung, and blood disease. Clinical populations of circadian misalignment (e.g., specific chronotypes, jet lag, night shift workers, genetic polymorphisms or risk variants that influence circadian rhythms), obesity (e.g., obese individuals, high fat diet), diabetes or diabetes risk (e.g., obese individuals, persons with impaired glucose tolerance, pre-diabetes, type 2 diabetes mellitus [T2DM]), and heart, lung, and blood disease/risk (e.g., hypertension, atherosclerosis, asthma) are of interest. Healthy individuals may be used where the focus is on investigating mechanisms or where a control group is needed. Circadian targeted intervention studies (e.g., behavioral, environmental [dietary or light] or pharmacological means) may be proposed where the primary focus is to elucidate circadian-dependent mechanisms.

National Heart, Lung and Blood Institute (NHLBI)

NHLBI will support research aimed to investigate circadian-mediated mechanisms contributing to the pathophysiology of human obesity, and/or obesity-coupled heart, lung, and blood disease.

Examples of research include, but are not limited to the following:

• Manipulate circadian alignment to investigate circadian-mediated mechanisms of obesity, as a cause of heart, lung and blood pathophysiology.
• Compare circadian-coupled physiology in metabolically healthy and unhealthy obese individuals. Studies are needed to elucidate the bidirectional relationships through which circadian biology contributes to obesity and obesity influences circadian function in the development of heart, lung, and blood pathophysiology.
• Investigate whether improving the amplitude of circadian rhythm mitigates obesity pathophysiology or enhances existing therapeutic approaches in managing obesity and obesity-related heart, lung and blood disease.
• Elucidate molecular and genomic pathways mediating the role of circadian biology in appetite/satiety signaling (e.g., leptin, ghrelin, endocannabinoids). Can the effects of circadian misalignment on satiety be offset by modifiers of circadian timing such as meal schedules?
• Elucidate circadian-coupled abnormalities in adipocyte physiology implicated in obesity pathophysiology such as adipokine secretion, adipocyte hyperplasia, insulin receptor signaling, and inflammation.
• Differentiate the susceptibility of vascular stress pathways (e.g., endothelial lipoprotein uptake, oxidative stress, monocyte trafficking, cytokine/chemokine signaling) to circadian misalignment in obesity. Identify circadian-mediated pathways differentiating obese individuals with versus without vascular pathophysiology and atherogenic risk. Does correcting circadian misalignment slow the progression of atherogenesis and intermediate markers of vascular disease in obese individuals?
• Determine whether the daily pattern of hemostasis factors (e.g., hepatic-derived fibrinogen and plasminogen; endothelial-derived PAI-1 and tissue factor) in conjunction with the daily pattern of obesity related inflammation increase the risk of thrombosis. Do these rhythms affect the efficacy of anti-thrombotic pharmacotherapy, and is thrombotic risk increased by circadian misalignment?
• Investigate whether asthma severity, nocturnal exacerbation, and/or treatment effectiveness are predicted by circadian phenotypes or circadian misalignment of lung immune/inflammatory response (e.g., immune cell types, cortisol level, metabolites). Does circadian misalignment of adipocytes in obese individuals with and without asthma increase risk or undermine the efficacy of pharmacology management?
• Elucidate circadian-mediated mechanisms of salt sensitivity in obesity-related hypertension (e.g., renal-angiotensin system; autonomic regulation; renal absorption). Does circadian misalignment alter the blood pressure response to salt reduction in obesity or in the context of weight loss?
• Investigate the coupling of the gut microbiome to pathways linked to cardiometabolic pathophysiology (e.g., atherogenesis, hypertension) and associated with obesity.
• Determine whether circadian misalignment promotes atherogenesis through modulation of the innate immune system in obesity.
• Elucidate circadian-coupled abnormalities in hematopoietic stem/progenitor cells (HSPCs) mobilization in blood stream and bone marrow microenvironment in obese individuals.
• Elucidate molecular relationships between high fat diet and CVD pathophysiology that are modified by circadian misalignment. Can therapeutic outcome be enhanced by improving circadian alignment?
• Investigate whether circadian phenotype can be used to personalize the medical management of metabolic risks in obese individuals with and without hypertension, hyperlipidemia, or insulin resistance.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIDDK will support research focused on elucidating circadian-dependent mechanisms of diabetes-related metabolism in humans, utilizing in depth phenotyping approaches.

The following research questions and approaches are examples of the type of application that would be of interest but are not intended to be inclusive:

• Elucidate circadian-dependent mechanisms of beta-cell function, insulin secretion, and insulin sensitivity by applying sophisticated, in depth phenotyping methodologies (e.g., glucose-potentiated arginine stimulation; hyperinsulinemic and/or hyperglycemic clamps; C-peptide kinetics; stable isotopes combined with euglycemic, hyperinsulinemic clamps; and/or continuous glucose monitoring).
• Identify circadian-coupled mechanisms of lipid, amino acid or protein synthesis, lipid deposition (e.g. hepatic triglycerides) or metabolism utilizing stable isotopes and/or NMR technology.
• Investigate the mechanistic contribution of circadian rhythms to regulation of proteins, signaling molecules, epigenetics, metabolomics and/or proteomics in isolated metabolically active tissue (e.g. adipose, muscle).
• Elucidate circadian-mediated mechanisms of autonomic nervous system activity, as well as markers of inflammation as potential mediators of pathophysiology in glucose tolerance, beta-cell function and insulin sensitivity.
• Circadian misalignment has been shown to decrease insulin sensitivity. It is not known if this effect is tissue specific (muscle versus hepatic) or a non-specific whole body phenomenon. How does circadian misalignment and alignment influence hepatic gluconeogenesis, whole body lipogenesis and hepatic fat storage in humans?
• Determine how circadian misalignment and alignment influence oxidative pathways, endoplasmic reticular stress, insulin signaling in human muscle and adipose tissue, and is this coupled with systemic changes in insulin sensitivity?
• Investigate whether dietary fat impairs circadian alignment independent of caloric intake as measured by signaling proteins in human adipose or muscle tissue and other measures of diabetes-related metabolism?
• Investigate the effects of bariatric surgery on circadian mediated mechanisms of diabetes-related metabolism utilizing deep metabolic phenotyping approaches.
• Investigate the mechanistic relationship between circadian alignment and misalignment and circulating branched chain amino acids and muscle metabolism.

Responsiveness

NHLBI is interested in research that elucidates circadian-dependent mechanisms of human obesity and/or obesity-coupled heart, lung and blood pathophysiology. NIDDK is interested in research investigating circadian-dependent mechanisms of diabetes-related metabolism in humans, using in-depth phenotyping and sophisticated measures of metabolism. Research supported by this FOA is intended to involve participation of human subjects. The FOA encourages the Multiple Program Director/Principal Investigator (PD/PI) application format to join the appropriate expertise in heart, lung, and blood; diabetes; and circadian research in team approaches.

The following types of research projects are not responsive to this FOA and will not proceed to review:

• Basic research involving animals, animal tissue, or human immortalized cell lines
• Studies of epidemiological risk and clinical trials to assess therapeutic efficacy, effectiveness, or implementation
• Studies limited to behavioral assessments of circadian rhythm (e.g., actigraphy) as a circadian function/mechanism
• Studies designed to investigate circadian-coupled heart, lung, or blood disease pathways without integrating obesity
• Studies proposing to assess glucose or glucose tolerance (e.g. oral glucose tolerance test or intravenous glucose test) in the absence of other more sophisticated measurements of metabolism
• Studies in which the primary outcome is weight-loss without the measurement of diabetes-related metabolism

Annual one-day, in-person meetings of study teams will be held in Bethesda, Maryland to present updates on study progress.

See Section VIII. Other Information for award authorities and regulations.

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

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) 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 SF424 (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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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 activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0270
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed. Budget requests should include travel for the PD/PI and key personnel to attend an annual one-day meeting of study teams in Bethesda, Maryland.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Clearly describe the scientific question/hypothesis under investigation with the overall aim to elucidate circadian-dependent mechanisms contributing to the pathophysiology of human obesity, obesity-coupled heart, lung or blood disease, or diabetes-related metabolism.

Research Strategy: Proposed research must include the participation of human subjects. Provide a justification of the proposed clinical sample, intervention strategy, circadian phenotyping, and outcome measures. Describe how the proposed study design will contribute significantly to understanding circadian-dependent mechanisms of obesity, obesity-coupled heart, lung or blood pathophysiology, and diabetes-related metabolism.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

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.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

All instructions in the SF424 (R&R) Application Guide must be followed.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to 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. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date 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 SF424 (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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(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. See Section III of this FOA for information on registration requirements.

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 System for Award Management. 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 and compliance with application instructions by the Center for Scientific Review and responsiveness by the National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. Applications that are incomplete, non-compliant, or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

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 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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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?

Specific to this FOA: To what extent will the proposed study significantly advance the understanding of circadian coupled pathophysiology in human (clinical) obesity and obesity-coupled heart, lung, and blood disorders?

Are the PD(s)/PI(s), 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?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA: How likely is it that the proposed approach will elucidate mechanisms of circadian-coupled pathophysiology contributing to human obesity, obesity-coupled heart, lung, and blood disease, or diabetes-related metabolism?

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?

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 score, but will not give separate scores for these items.

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 Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

Not Applicable

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 score.

Not Applicable

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).

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) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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 the National Heart, Lung, and Blood Institute in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

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 Heart, Lung, and Blood Advisory Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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’s 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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this 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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)

Telephone: 301-945-7573

Aaron D. Laposky PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0193
Email: [email protected]

Karen Teff, PhD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8803
Email: karen.teff@nih.gov

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: [email protected]

Andre Walker
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: [email protected]

Diana O'Donovan
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8868
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 Part 75.