and Human Services (HHS)
EXPIRED
Participating Organization(s) |
National Institutes of Health (NIH) |
National Institute on Alcohol Abuse and Alcoholism (NIAAA) |
|
Funding Opportunity Title |
Circadian Rhythms and Alcohol-induced Tissue Injury (R21) |
Activity Code |
R21 Exploratory/Developmental Research Grant Award |
Announcement Type |
New |
Related Notices |
None |
Funding Opportunity Announcement (FOA) Number |
PA-11-179 |
Companion FOA |
|
Catalog of Federal Domestic Assistance (CFDA) Number(s) |
93.273 |
FOA Purpose |
This Funding Opportunity Announcement (FOA) encourages applications that propose to conduct mechanistic studies of the circadian rhythms involved in alcohol-induced organ damage. The circadian system comprises of a complex feedback network that involves interactions between the central nervous system and peripheral tissues. The effects of alcohol on circadian rhythm and how alcohol’s action is modulated by circadian rhythms have key implications for alcohol research. The central and peripheral oscillators, either individually or together, may play an important role in alcohol-induced tissue injury. The objective of this FOA is to understand the molecular mechanisms of alcohol-induced tissue damage that involve central and peripheral circadian rhythms, particularly their connection with metabolism and metabolic disorders. |
Posted Date |
March 24, 2011 |
Open Date (Earliest Submission Date) |
May 16, 2011 |
Letter of Intent Due Date |
Not Applicable |
Application Due Date(s) |
Standard dates apply, by 5:00 PM local time of applicant organization. |
AIDS Application Due Date(s) |
Standard dates apply, by 5:00 PM local time of applicant organization. |
Scientific Merit Review |
Standard dates apply |
Advisory Council Review |
Standard dates apply |
Earliest Start Date(s) |
Standard dates apply |
Expiration Date |
May 8, 2013 |
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
This Funding Opportunity Announcement (FOA), issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) encourages Exploratory/Developmental Grant (R21) applications that propose to conduct mechanistic studies of the circadian rhythms involved in alcohol-induced organ damage. The circadian system comprises of a complex feedback network that involves interactions between the central nervous system and peripheral tissues. The effects of alcohol on circadian rhythm and how alcohol’s action is modulated by circadian rhythms have key implications for alcohol research. The central and peripheral oscillators, either individually or together, may play an important role in alcohol-induced tissue injury. The objective of this FOA is to understand the molecular mechanisms of alcohol-induced tissue damage that involve central and peripheral circadian rhythms, particularly their connection with metabolism and metabolic disorders.
Related Funding Opportunity: Investigators, who are interested in proposing discrete, specified, circumscribed projects based upon strong preliminary data, should submit applications in response to the partner FOA of identical scientific scope (PA-11-178), which uses the NIH Research Project Grant (R01) funding mechanism.
The circadian rhythm system orchestrates the temporal organization of many aspects of physiology. The circadian system is comprised of a complex feedback network involving interactions between the central nervous system and peripheral tissues. The central clock in the brain uses specific biochemical and neural pathways to pass its circadian signals along to other organs, such as the liver or heart. In the past two decades, major progress has been made to understand the molecular mechanisms of circadian rhythms. Recent studies have also revealed that circadian system affects metabolic homeostasis while metabolic pathways feed back into the regulation of circadian system and modulate many physiological processes and behavior.
The Central and Peripheral Circadian Rhythms
The control center for the mammalian central circadian rhythm is located in the anterior hypothalamus, which governs functions such as sleep, hormone production, and metabolism. A cluster of several thousand neurons called the suprachiasmatic nucleus (SCN) controls a wide range of physiological variations. Each neuron in the SCN is an autonomous cellular circadian clock, which normally act in unison as a master pacemaker for the organism. The retino-hypothalamic tract connects signals from the retina to the SCN, and mediates a close coupling between the SCN and the light/dark cycle as perceived by the eye.
The molecular mechanisms for generating circadian oscillations by SCN consist of a set of interlocking feedback loops involving transcriptional and translational regulation. The centerpiece of this regulatory network in mammals is the heterodimer of transcription factor CLOCK and BMAL1, which activates transcription of the Period (Per) and Cryptochrome (Cry) genes. PER and CRY proteins can interact with each other, or with other proteins such as casein kinase Iε (CKIε). Then, the PER/CRY complex translocates into the nucleus to inhibit CLOCK/BMAL1 transactivation activity, which in turn results in the repression of the Per and Cry genes. If the PER/CRY complex is released, by degradation through ubiquitination and protesome, its repression of CLOCK/BMAL1 can be relieved, and then the negative feedback loop can start again. This feedback loop is also connected and modulated by many other feedback loops, such as the one involving the orphan nuclear receptors REV-ERBα and RORα, in order to respond or regulate many biological processes it involves.
Early studies of central circadian rhythms were based on behavioral assays, such as locomotor activity. Although many aspects of peripheral tissues, such as circulating and intracellular metabolites, feeding-related hormones, and ingestive behaviors, are known for many years to exhibit rhythmicity, the peripheral circadian clocks could not be studied mechanistically because of the lack of molecular markers for their rhythmicities. Recent identification of key circadian players that are cycled at the mRNA level has provided necessary markers for rhythmicity in peripheral tissues. Studies using these markers have shown that many aspects of rhythmicities in peripheral tissues are driven, at least in part, by circadian clocks. In fact, every mammalian tissue tested so far has been demonstrated to possess the capacity to generate circadian oscillations. Gene expression patterns of rhythmic genes in different tissues are different, with varying degrees of overlap, suggesting that circadian genes are regulated in a tissue-specific manner. This characteristic of circadian gene expression patterns reflects the unique functions of each peripheral cell or tissue.
Peripheral oscillators depend on various metabolic, endocrine, and neural cues. Disrupting these temporal relationships within a tissue has been increasingly recognized as an important cause of tissue damage. Although the role of peripheral clocks in tissue injury remains unclear, it is likely that these peripheral oscillators are important for driving local rhythms in a physiologically relevant and tissue-specific fashion.
Interaction between Central and Peripheral Circadian Rhythms
The clock in the hypothalamic SCN is the master pacemaker , which drives behavioral rhythms and also coordinates the many peripheral clocks to maintain proper phase relationships with each other. The peripheral clocks appear to interact with the central clock in a hierarchical manner, with the SCN clock acting as the master regulator. The SCN drives rhythmic behavior and coordinates the many peripheral clocks through various humoral and neural signals. The peripheral circadian rhythms are controlled at multiple levels, by receiving entraining cues centrally from the SCN, and also from their own local cell-autonomous oscillators, operating independently of the SCN. Peripheral metabolic tissues such as liver respond to various metabolic signals, and the CNS coordinates these peripheral events either directly or indirectly. For example, CNS regulates food intake and energy expenditure. On the other hand, feeding signals can also entrain peripheral clocks with great efficacy.
It is still not clear how metabolic signals communicate with the SCN circadian control. It has been known that receptors for leptin and ghrelin are present on SCN cells, and it is likely that these important metabolic peptides interact directly with the SCN. Adding ghrelin to SCN slices or SCN explants in vitro caused phase shifts in Per2-reporter gene expression. It is also known that leptin and ghrelin affect the circadian clock in the SCN to coordinate the temporal secretion patterns of NPY, a potent appetite stimulant showing both ultradian and circadian rhythms. NPY is regulated by the SCN clock, and also feeds non-photic signals back to the SCN. Furthermore, both histaminergic and serotonergic signaling pathways, involved in feeding and energy metabolism in the hypothalamus, have been shown to modulate SCN oscillations and sleep. These signaling pathways appear to be involved in the feedback loop connecting feeding and metabolic state to the SCN.
The discovery that cell-autonomous circadian clocks exist throughout the peripheral tissues of all mammals has provided a radical perspective in our view of the circadian system. The previous view that the SCN pacemaker alone generates and drives rhythms throughout the body is now supplemented by the findings that that all tissues have circadian oscillators and these peripheral oscillators interact with central clock in the SCN to regulate various biological functions. These central and peripheral oscillators, either individually or together, may play an important role in alcohol-induced tissue injury.
Circadian Rhythms and Metabolism
Circadian rhythms extensively control the metabolic networks at the levels of transcription, translation, and posttranslational modification. Metabolism in the liver can be greatly affected by circadian rhythms and changes in feeding status. A large number of metabolic enzymes, such as cytochrome P450s, ADH, ALDH, as well as enzymes involved in heme biosynthesis and mitochondrial function, are regulated by circadian clock. Many other important metabolic pathways such as glycolysis, fatty-acid metabolism, cholesterol biosynthesis, and xenobiotic and intermediate metabolism are also under circadian regulation. The rate-limiting steps of these metabolic pathways are often the target sites of circadian control. Because of their important roles in metabolism, mutations in the clock genes often cause metabolic disorders. For example, a mutation of the Clock gene has been found to cause mice to be hyperphagic and obese. Also, a different mutation in the Clock gene has been found to facilitate cholesterol accumulation in the liver of mice that were fed with a cholesterol and/or cholic diet. Furthermore, both Clock mutant mice and Bmal1 knockout mice have been found to be hypersensitive to insulin shock, indicating a direct role for circadian rhythm in regulating glucose homeostasis.
The circadian rhythms, both central and peripheral, interact with metabolism in a very complex manner. Whereas the circadian systems play an important role in metabolism, as discussed above, metabolism itself can also affect the function of clock genes and circadian rhythms. The effects of metabolism on circadian rhythms are supported by the following two important lines of investigations. (1) Circadian clocks can be entrained by various metabolism-related external cues, such as food intake and alcohol consumption. The liver circadian rhythms respond particularly rapidly to food intake. For example, a recent study has demonstrated that a high-fat diet in mice can change both the rhythm of the locomotor activity and expression of clock genes and clock-controlled genes. (2) Many transcription factors, which include the nuclear receptors known to play diverse roles in regulating metabolism, exhibit rhythmic expression patterns and sense various lipids, vitamins, and fat-soluble hormones. Recent studies have shown that 28 of 48 nuclear receptors examined in mice display circadian expression in various tissues. Some of these rhythmic nuclear receptors, such as PPARα, PPARγ, glucocorticoid receptor, RARα, and RXRα, have been directly connected to the key components of the circadian system. Many of these nuclear receptors have been also implicated in alcohol-induced tissue injury. The vascular PPARγ is now known to control circadian rhythms of blood pressure and heart rate through BMAL1. Recently, PGC-1α, the coactivator of nuclear receptor PPAR, has been shown to play an important role in circadian regulation. PGC-1α stimulates BMAL1 expression. Knockdown of PGC-1α expression in liver disrupts rhythmicity, indicating its essential role for normal liver circadian function. PGC-1α is sensitive to many environmental factors such as nutritional status, activity, and body temperature, and it regulates adaptive energy metabolism in many peripheral tissues. Many internal and external cues, such as nutrients (sterols, lipids, and/or carbohydrates) and humoral signals (insulin, glucocorticoid, and perhaps incretin), have been shown to contribute to the entrainment of rhythmicity. PGC-1α has been proposed to be a key coupling component between metabolic signals and circadian system.
Circadian Rhythms and Redox State
The redox state of cells plays an important role in the function of the circadian rhythm. Among rhythmic metabolic substrates in the liver, the ratio of NADP+ to NADPH exhibits one of the most dramatic fluctuations. The presence of NADH or NADPH promotes binding of the heterodimeric clock transcription factor complexes to DNA. The transcription factors NPAS2 or CLOCK may function as redox sensors in the cell. NADH and NADPH have been shown to stimulate the DNA-binding activity of the NPAS2-BMAL1 heterodimers, whereas NAD+ and NADP+ inhibit the DNA-binding activity. Metabolic activities leading to changes in NAD+ levels may also impact the circadian rhythms. In fact, lactate, which decreases the ratio of NAD+/NADH via lactate dehydrogenase, has been shown to activate NPAS2-BMAL1-dependent gene expression when added to the medium of cultured cells. Since alcohol intake also alters the NAD+/NADH ratio and increases lactate production, it is reasonable to hypothesize that alcohol may affect the liver circadian rhythms by altering the redox state in the liver. SIRT1, a NAD+-dependent histone deacetylase, may be involved in the integration of circadian and metabolic transcription networks. SIRT1 interacts directly with CLOCK and deacetylates BMAL1 and PER2. In fact, circadian protein CLOCK itself functions as a histone acetyltransferase (HAT). The known targets of CLOCK-mediated HAT activity now include histone H3, H4, BMAL1, and PER2, all of which display cycles of acetylation. Both PER2 and BMAL1 have been shown to be more stable when acetylated. SIRT1 activity also cycles, with peak activity in the early evening, suggesting a potential role for a rhythmic input to the circadian clock. Since cellular NAD+ levels are coupled to metabolic activity, NAD+-dependent histone deacetylase SIRT1 and histone acetyltransferase CLOCK may serve as two key players in the connection between circadian rhythms and metabolism.
Taken together, both central and peripheral circadian systems are intimately connected to metabolism in order to coordinate many biological processes in response to the cyclic environment. The integration of circadian and metabolic cycles may optimize energy utilization, and disruption of the rhythmicities in either circadian oscillators or metabolic pathways could cause metabolic disorders.
Circadian Rhythm and Alcohol-induced Disorders
Since the 1960's, the effects of acute and chronic alcohol ingestion on sleep have been extensively studied. During drinking and withdrawal periods, alcoholics often experience problems falling asleep and experience a decrease in total sleep time compared to non-alcoholics. Conversely, disrupted circadian rhythms may predispose people to develop alcohol-related problems or relapse among abstinent alcoholics.
It has been well-documented in humans and animal models that both acute and chronic alcohol intake can affect many aspects of circadian rhythms, including physiological, endocrine, and behavioral functions. (1) Alcohol intake and withdrawal have been shown to affect the circadian rhythms of body temperature in rats, and alter circadian melatonin secretion in both healthy and alcoholic people. (2) A study in C57BL/6J mice has shown that chronic alcohol intake and withdrawal significantly disrupt circadian clock photic phase-resetting and daily locomotor activity. (3) Alcohol intake has been found to produces changes in SCN and alter the circadian expression of Per2 and Per3 in SCN, suggesting that alcohol may directly affect the central pacemaker and interfere with its circadian functioning. Neonatal alcohol exposure in rats during the brain growth spurt can alter clock gene oscillations in the liver, in addition to the SCN. (4) The expression of clock genes in male alcoholic patients are significantly reduced in the peripheral blood mononuclear cells. Even in healthy people, the expression of clock genes in peripheral blood cells are associated with alcohol consumption.
Studies have also shown that alcohol sensitivity and preference may change with disrupted circadian timing, as shown in the following examples. (1) Alcohol intake in rodent peaks during their active dark period, but this can be altered by experimental manipulation, such as the shift of light/dark cycle. (2) In high alcohol-drinking rats, repeated light-dark phase shifts modulate their voluntary ethanol intake. (3) A study has shown that PER2 affects the glutamatergic system and influences the ethanol-consumatory behavior. Per2 expression also regulates alcohol sensitivity during the beginning of the inactive phase in mice. (4) In human, the increased risk of relapse for drinking is associated with insomnia and other sleeping problems. In rodent models, chronic alcohol intake has also been associated with sleeping problems and phase-resetting. A genetic variation of PER2 gene has been found to be significantly associated with alcohol consumption in Swedish adolescents sleeping problems. A haplotype of CLOCK gene is also associated with comorbid alcohol use and depressive disorders.
Despite the fact that there is no direct evidence to connect circadian rhythms and alcohol-induced organ damage, many non-alcohol studies have suggested indirectly that circadian rhythms may play an important role in alcohol-induced tissue injury. This hypothesis that circadian rhythms are involved in alcohol-induced tissue injury is supported by the following four lines of research. (1) First, dysfunctions of circadian rhythms are involved in many diseases that are known to be modulated by alcohol. For instance, some genetic variations of the Clock gene are associated with obesity and metabolic syndrome. Mutations in many other clock genes have also been found to be associated with obesity, diabetes, aging, and metabolic disorders. The circadian expression of the key clock genes have been found to be disrupted in hepatocellular carcinoma patients. (2) Secondly, some metabolic enzymes involved in alcohol-metabolism are affected by circadian rhythms. For example, cytochrome P450, ADH, ALDH, as well as enzymes involved in heme biosynthesis and mitochondrial function are affected by circadian oscillators. (3) Thirdly, some biological pathways closely related to alcohol’s actions are involved in, or affected by, circadian rhythms. Some of these pathways, such as the ones involving SIRT1, PPARs, PGC-1α, AMPK, NPY, and NAD+/NADH ratio, have been discussed above. Malondialdehyde, a marker of oxidative stress affected by ethanol, is found to exhibit circadian patterns of expression in the liver, kidney, and plasma of mice. (4) Lastly, LPS, which is increased in blood after alcohol consumption, suppresses clock genes, suggesting that circadian rhythms play an important role in response to systemic inflammatory stimulation.
Given the strong links between the circadian components and alcohol’s role in these physiological processes, it is very likely that circadian rhythms, both central and peripheral, play a critical role in alcohol-induced organ damage. The effects of alcohol on circadian rhythm and how alcohol’s action is modulated by circadian rhythms may have key implications for understanding alcohol’s action in tissue injury. Studying the role of circadian rhythms in alcohol-induced organ damage will provide many missing links in our understanding of the underlying mechanisms. With the knowledge that circadian oscillators are cell autonomous and distributed throughout the body, it is important to investigate both central and peripheral circadian rhythms for their connection with alcohol-induced tissue injury. In future alcohol studies, it will be necessary to consider the impact of circadian variations on the experimental design, phenotype assessment, sample collections, and molecular characterizations, in normal or diseased conditions. Furthermore, circadian variations could have important implications for therapeutic development and treatment of alcohol-induced disorders because of their actions on metabolic or physiological pathways. Recent advances in the molecular study of circadian systems, particularly their connection with metabolism and metabolic disorders, have provided us an unprecedented opportunity for studying alcohol-induced organ damage.
Research Objectives:
Appropriate topics include but are not limited to:
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 |
The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications. |
Award Budget |
The total project period for an application submitted in response to this funding opportunity may not exceed 2 years. Although the size of award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/developmental project; direct costs are limited to $275,000 over an R21 two-year period, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period. 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. |
Award Project Period |
1-2 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. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the SF 424 (R&R) Application Guide.
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.
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, with the following additional instructions:
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.
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, NIH. Applications that are incomplete will not be reviewed.
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.
The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.
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?
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
For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
Renewals
Not Applicable
Revisions
For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.
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) (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. Following initial peer review, recommended applications will receive a second level of review by the appropriate advisory council or board. 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]
Q. Max Guo, PhD
National Institute on Alcohol Abuse and Alcoholism ( NIAAA)
Telephone: 301-443-0639
Email: [email protected]
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Judy Fox
National Institute on Alcohol Abuse and Alcoholism ( NIAAA )
Telephone: 301-443-3891
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.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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