of Health and Human Services
National Institutes of Health (NIH), (http://www.nih.gov)
Components of Participating Organizations
National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov)
Title: Alcohol Tolerance: Contribution to Consumption (R01)
NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide.
APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.
This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).
A registration process is necessary before submission and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. See Section IV.
Request For Applications (RFA) Number: RFA-AA-08-009
Catalog of Federal Domestic Assistance Number(s)
Release/Posted Date: January 16, 2008
Opening Date: February 25, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): February 25, 2008
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Submission/Receipt Date(s): March 25, 2008
AIDS Application Submission/Receipt Date(s): Not Applicable
Peer Review Date(s): July/August 2008
Council Review Date(s): August 2008
Earliest Anticipated Start Date(s): September 30, 2008
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: March 26, 2008
Due Dates for E.O. 12372
Table of Contents
1. Research Objectives
It is well established that tolerance develops to the effects of alcohol. In fact, tolerance is one of several criteria used for diagnosing alcohol dependence according to DSM IV. However the consequences of alcohol tolerance for health and for the development of alcohol dependence have not been determined. Tolerance may permit greater consumption of alcohol as a consequence of reduced adverse response to alcohol. Consequently with greater alcohol consumption greater tissue damage would result. In addition the greater consumption permitted by alcohol tolerance may influence the development of alcohol dependence. In order to establish the relevance of tolerance for development of treatments for prevention of relapse or treatment of alcohol dependence, the significance of tolerance to alcoholism needs to be clarified.
Extensive studies have been carried out on alcohol-induced tolerance and have demonstrated that alcohol tolerance is a complex phenomenon that encompasses a wide range of alcohol-induced responses and a multitude of distinct processes. The emphasis of this funding opportunity announcement focuses on the relationship between tolerance to alcohol induced response and increased risk for alcohol dependence or relapse. Once such a link is established, the mechanism of tolerance can be explored for those specific responses predicting or associated with dependence or relapse.
Forms of Tolerance
Tolerance to alcohol is not a simple process that occurs in all cells by the same mechanism. First, tolerance is not a universal response to alcohol. Some responses, for example locomotor activation, do not exhibit tolerance. Secondly, the characteristic features of tolerance vary depending on the specific biological response. Tolerance can develop in the absence of alterations in alcohol metabolism and this form is referred to as functional tolerance. It is expressed in at least three time domains: acute -occurring during alcohol exposure, rapid-occurring within 24 to 36 hours of exposure to alcohol and chronic tolerance resulting from prolonged or repeated exposure to alcohol. In addition metabolic tolerance that involves increased metabolism of alcohol can develop after chronic exposure to elevated blood levels of alcohol.
Functional tolerance refers to lessened response to alcohol independent of the rate of metabolism of alcohol. Three time domains have been identified and some evidence suggests that different mechanisms are involved with the development of tolerance over each time period. Tolerance that develops during a single exposure to alcohol is referred to as acute functional tolerance or within session tolerance. For example following administration of sufficient alcohol, experimental animals lose the ability to maintain an upright position and fall over. With time the individuals recover and regain the ability to right themselves. The blood alcohol concentration at loss of righting is found to be lower than the concentration at which the animals recover the ability to right themselves. This difference in blood alcohol concentration is interpreted to represent the development of tolerance to alcohol within the single exposure period. Rapid functional tolerance refers to the lessened response following a second exposure to alcohol at a time after the complete metabolism of an initial dose of alcohol. Chronic tolerance develops after repeated and/or chronic exposure to alcohol.
Initial Alcohol Exposure: Relationship between Sensitivity and Tolerance
Comparison of the response among different individuals within a population to an initial exposure to alcohol demonstrates that there is a wide variation in the degree of response. The variation is, in part, genetically determined. A lower response to an initial alcohol experience has been associated with increased risk for alcohol dependence. The low initial response has been described as “innate tolerance” or low sensitivity. It has been suggested to involve two components: an innate sensitivity and an acute tolerance that occurs during the rising blood concentration of alcohol.
Current evidence suggests that the alcohol sensitivity and tolerance components of the low response to alcohol are not necessarily related. In rat strains that exhibit the same initial response to alcohol differences in acute tolerance can be observed. This indicates that sensitivity and acute tolerance can be distinguished. Typically tolerance implies that a reduced response to alcohol results from a prior exposure to alcohol.
Tolerance over the Lifespan
An additional feature of tolerance is that it can vary is not over the life span. Adolescents exhibit lower sensitivity to sedative and motor effects of alcohol, but higher sensitivity to effects on learning, memory, and social behaviors. Some of these characteristics have been attributed to accelerated tolerance development in adolescents. Acute tolerance to the sedative effects of alcohol is readily observed in adolescent rats; however, with age the magnitude of acute tolerance lessens. Whereas acute tolerance was observed within the first exposure to alcohol in adolescent rats, it was not in adult rats. It has been proposed that acute tolerance declines with age but that this phenomenon is modified by stress or alcohol exposure such that the decline in tolerance development does not occur in adult animals with a history of alcohol exposure or those subjected to stress. In contrast to acute tolerance, rapid tolerance to the sedative effects of alcohol was not observed during preweanling and periadolescence. However preweanling rats do develop tolerance to the motor impairing effects of alcohol following chronic alcohol administration. There is only limited information regarding the genetic, molecular, and cellular mechanisms that contribute to adolescent sensitivity and tolerance to alcohol.
Tolerance following Chronic Alcohol Exposure
Following chronic or repeated exposures to alcohol many alcohol-induced responses exhibit tolerance. This process, which represents long term adaptation to alcohol, is poorly defined but is an area of active investigation. During chronic exposure to high intake of alcohol metabolic tolerance may develop. Alcohol is metabolized by the gut and primarily the liver. While hepatic alcohol dehydrogenase accounts for much of alcohol metabolism, gene expression is not induced at concentrations commonly achieved during alcohol consumption in humans. In contrast during chronic alcohol consumption the microsomal ethanol oxidizing system (MEOS) is induced four to ten fold and can account for increased removal of ethanol at high blood concentrations, Km = 10 mM. The MEOS is comprised of the P450 enzymes CYP2E1, CYP1A2 and CYP3A4. Consequently increased metabolism of alcohol is likely to play a role in tolerance only during chronic alcohol consumption. In this instance the lessened response is due to less circulating alcohol as a consequence of its more rapid metabolism.
Potential Mechanisms Involved In Functional Tolerance
Although the phenomenon of tolerance to alcohol has been described, much less is known about the mechanisms that are involved in tolerance. The diverse forms of tolerance add to the complexity since current evidence suggests that separate mechanisms may be involved in the different forms of tolerance.
Acute Functional Tolerance
Alcohol exposure in vivo induces tolerance to alcohol augmentation of muscimol stimulated chloride flux into cerebellar membrane vesicles in vitro with a time course consistent with acute tolerance. Subsequently, alcohol has been implicated to act through protein kinase epsilon and protein kinase epsilon phosphorylation to modify this GABA receptor response. Since tolerance for motor impairment occurs in association with tolerance to the GABA receptor response, it has been proposed that these biochemical alterations may have a role in acute functional tolerance development for the motor impairing effects of alcohol.
At the level of neurocircuitry the mesolimbic serotonergic pathway has been implicated in acute tolerance development. Lesions of the medial but not the dorsal raphe nucleus delayed acute tolerance development to the motor impairing effect of alcohol.
Rapid Functional Tolerance
Rapid tolerance was first described for the hypothermic effects of alcohol in mice. It was characterized to exhibit a dose response relationship and a duration of only one day. Subsequently other responses have been observed to exhibit rapid tolerance. A characterization of rapid tolerance development for both motor impairment and hypothermia revealed that the extent of rapid tolerance for both responses was dose dependent.
Pharmacological blockade of several neurotransmitter or neuromodulatory receptors have been found to interfere with rapid tolerance development. Antagonist of adenosine A1 receptors and dopamine D1 receptors eliminated rapid tolerance development as does ketamine, a nonspecific NMDA receptor antagonist. Administration of the opioid antagonist naltrexone systemically or directly into the shell or core of the nucleus accumbens blocked rapid tolerance to the motor impairing response of alcohol. The GABA B receptor agonist, baclofen blocked tolerance while two specific GABA B receptor antagonists facilitated tolerance development. Furthermore, the GABA B receptor agonist reversed the action of the receptor antagonists.
Signal transduction mechanisms have been identified in rapid tolerance development. The nNOS knock out mouse fails to develop rapid tolerance to the hypothermic response to alcohol and an inhibitor of NOS, administered intraventricularly, blocked tolerance development to the hypothermic and motor impairing effects of alcohol. NOS generates NO which can stimulate soluble guanylyl cyclase resulting in the generation of cyclic GMP. Four different inhibitors of guanylyl cyclase administered intraventriculary blocked alcohol-induced rapid tolerance for motor impairment while agents that mimic cyclic GMP or increase cyclic GMP enhanced tolerance.
The mechanisms involved in development of chronic tolerance are not clearly resolved. It has been difficult to separate those mechanisms responsible for chronic tolerance from the many neuroadaptations that occur during chronic alcohol exposure. However, there is evidence that the mechanisms involved in acute functional tolerance are distinct from those of chronic tolerance.
Recent evidence suggests that exposure to alcohol and other drugs of abuse alter the amount and types of genes expressed in specific brain regions. CREB and related proteins are transcription factors that mediate effects of the cAMP second messenger pathway on gene expression. Increased CREB function induced by viral vector injection into the nucleus accumbens decreased animals’ sensitivity to the rewarding effects of morphine and cocaine. This suggests that CREB activation mediates, in part, tolerance to morphine and cocaine. Alterations in CREB activity have been observed following acute and chronic alcohol exposure. The role of CREB and other transcription factors in the development of tolerance to alcohol, particularly as it relates to alcohol consumption and alcohol dependence, are undetermined.
Influence of Genetic Variation on Tolerance Development
There is a genetic contribution to the development of tolerance. Several laboratories have noted differences in development of acute tolerance in different mouse strains and selectively bred rats. Subsequently strains of mice that show no tolerance or high tolerance to the hypothermic effect of alcohol have been bred. The genes which contribute to the variation in tolerance can provide information about the mechanisms and pathways that participate in tolerance formation.
Using differences in tolerance development, QTL analysis has indicated chromosome regions that contribute to response variation. QTL analysis was used to suggest candidate genes for tolerance and then microarray analysis was performed to test for differences in expression of these candidate genes. A signal transduction cascade involving the glutamate receptor delta2 protein, the Ephrin B3 ligand, the NMDA receptor, the zinc finger protein 179 and peroxiredoxin may participate in acute tolerance to the motor impairing effect of alcohol. These changes suggest that alcohol exposure leads to phosphorylation of the NMDA receptor and its translocation resulting in resistance to the inhibitory effects of alcohol.
In addition to rodent studies, insight into mechanisms of tolerance has been provided by studies in the fruit fly, Drosophila melanogaster. It has been used as a model for alcohol response because it can be readily manipulated with genetic techniques. Tolerance to alcohol-induced sedation has been shown to exhibit both rapid and chronic tolerance in the fruit fly. A gene knockout approach showed that rapid tolerance requires the neurotransmitter octopamine. This amino acid transmitter is considered homologous to the mammalian transmitter norepinephrine. Also necessary is the protein product of the Hang gene and the slowpoke gene which codes for a calcium activated potassium channel. Protein synthesis is not required for expression of rapid tolerance. In contrast, chronic tolerance requires protein synthesis and the protein product of the Hang gene, but octopamine is not necessary. Chronic and rapid tolerance are additive.
Underlying tolerance is a change in the processing of the response to alcohol. This adaptation has been assumed to involve a modification in signal transduction. Some of the many changes following alcohol exposure may be involved in this neuroadaptation and account in part for tolerance. However, the specific changes responsible for tolerance are not as yet established. Research noted above indicates that disruption of various signal transduction pathways or neural circuits will interfere with tolerance. Such evidence implicates those pathways in the response to alcohol but it does not necessarily indicate that the experimental disruptions are the locus of adaptation during tolerance nor are they necessarily changed during tolerance. The responsible alcohol-induced alterations could be elsewhere in the pathway or circuit.
Tolerance, Learning and Memory
While much of the investigation on tolerance has approached this process from the perspective of cellular or neural circuit adaptation to alcohol, another conceptualization has considered the process of tolerance as a learning experience, one in which an association is made between the alcohol response and its anticipated physiological consequences. The historic evolution of concepts involved in tolerance to alcohol has been reviewed by Kalant in 1998. Rats trained to perform a task under the influence of alcohol perform better in subsequent trials. In contrast a control set of rats exposed to the same amount of alcohol but at a time unrelated to the task training, do not perform the task as well during a test trial with alcohol. This process of intoxication practice is interpreted as learning phenomenon. These findings as well as many more recent observations form the basis for the conditioning model of tolerance. Subsequent investigation has shown that external environmental cues are conditioned to the alcohol response and are employed in the tolerant response. Tolerance will develop to alcohol; however if the setting is changed in a subsequent trial– a novel room or other novel cues – the response to the test administration shows less tolerance. In addition to conditioning to external cues, there is evidence that under certain circumstances conditioned tolerance can develop to internal cues. Rats given a small dose of ethanol, that has no measurable effect on performance, prior to a high dose can condition the response to the high dose.
Conditioned tolerance has been shown to involve a learning process during which the organism learns to respond to ethanol by initiating actions opposite to those induced by ethanol and that compensate for the effect of alcohol. Rats injected with alcohol developed tolerance to the hypothermic effects. When these tolerant rats were injected with saline they responded with a hyperthermic response which would have counteracted the hypothermic response had the injection been alcohol as previous injections had been.
Additional mechanisms may also be involved. Tolerance has been proposed to result from the disposition of alcohol. Following repeated daily injections of ethanol in a familiar environment, a subsequent administration of ethanol produces lower brain and blood alcohol when it occurs in the similar rather than a novel environment.
Facilitation of Tolerance Development by Vasopressin
Neuropeptides have been found to modify the duration of alcohol-induced tolerance. This involves the development of a long lasting tolerance from a single exposure to alcohol when alcohol is paired with vasopressin. A single injection of alcohol induces acute tolerance during the alcohol exposure period and rapid tolerance for up to 36 hours after its metabolism is complete. No further indications of tolerance have been observed to persist beyond that time period. However when the initial injection of alcohol is combined with central injection of vasopressin and then the animal is subjected to practice trials of testing for motor impairment, a lasting tolerance develops and persists for as long as four weeks. It has been suggested that the ability of vasopressin to initiate tolerance for alcohol-induced motor impairment may involve a learning component in the testing for motor impairment. However not all responses are similarly affected. While vasopressin was able to induce long term tolerance to the motor impairing response to alcohol, tolerance was not induced to two other responses to alcohol, loss of righting reflex or hypothermia.
Noted even earlier were the effects of arginine-vasopressin on chronic tolerance. Daily systemic injection of arginine vasopressin given to mice during alcohol exposure for seven days and also during the withdrawal from alcohol was found to prolong the tolerance of the hypothermic and sedative response to a challenge injection of alcohol during the withdrawal period. The prolongation of tolerance persisted during withdrawal for as long as arginine vasopressin was administered. Arginine vasopressin appeared to maintain tolerance once it was developed since injection during just the withdrawal period was still effective in prolonging tolerance. Further investigation has shown that arginine vasopressin acts within the CNS at V1 vasopressin receptors and requires an intact noradrenergic and a serotoninergic system in its modulation of alcohol tolerance. This action of vasopressin may reflect a physiological process in which tolerance to alcohol is modulated by the learning and memory enhancing effects of this neuropeptide. V1 vasopressin receptor antagonists shorten alcohol tolerance and Brattleboro rats which have a genetic mutation resulting in deficient vasopressin are reported to not exhibit alcohol tolerance.
Potential Role of Tolerance in Alcohol Dependence or Relapse
In attempting to explain the transition of alcohol consumption from social drinking to impulsive drinking and then compulsive drinking with loss of control, it has been suggested that increased and continued alcohol consumption might in part be driven by a tolerance to the rewarding or reinforcing effects of alcohol. However, this hypothesis is not well supported by current evidence. The firing rate of the VTA dopaminergic neurons implicated in establishing the incentive salience of an experience is not different from control after chronic alcohol exposure and further the firing rate in response to alcohol is greater than in the naïve animal. When conditioned place preference was used as an index of the rewarding effect of alcohol, no indication of tolerance was observed following repeated exposure to alcohol. Rather if tolerance has a role in facilitating increased consumption, loss of control and inability to remain abstinent, the tolerance to the aversive responses to alcohol could be involved. Tolerance has been shown to conditioned place aversion and conditioned taste aversion. However the consequences of tolerance on reinforcing effects of alcohol, on the adverse effects of alcohol and conditioned learning of tolerance have not been linked to increased risk for dependence or increase relapse.
Objective and Scope
The goal of this initiative is to determine whether tolerance to a specific alcohol induced response has an effect on risk for alcohol dependence or relapse
Examples of research areas appropriate to this announcement include, but are not limited to:
See Section VIII, Other Information - Required Federal
Citations, for policies related to this announcement.
Section II. Award Information
1. Mechanism of Support
This Funding Opportunity Announcement (FOA) will use the NIH Research Project Grant (R01) award mechanism. The applicant will be solely responsible for planning, directing, and executing the proposed project.
This FOA uses “Just-in-Time” information concepts. It also uses the modular as well as the non-modular budget formats (see the “Modular Applications and Awards” section of the NIH Grants Policy Statement. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, “Modular Budget Component,” of the Application Guide).
U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research and Related Budget component found in the application package for this FOA. See NOT-OD-06-096, August 23, 2006.
Renewal (formerly “competing continuation”) applications will not be accepted. At this time, it is not known if this FOA will be reissued.
2. Funds Available
Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the Institutes and Centers (ICs) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.
The NIAAA intends to commit approximately 2 M dollars in FY2008 to fund 3-5 applications.
grants policies as described in the NOT-OD-05-004,
November 2, 2004.
Section III. Eligibility Information
1. Eligible Applicants
1.A. Eligible Institutions
You may submit an application(s) if your institution/organization has any of the following characteristics:
1.B. Eligible Individuals
Any individual 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.
More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach that clearly does not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).
The decision of whether to apply for a single PD/PI or multiple PD/PI grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for multiple PD/PI grants will require additional information, as outlined in the instructions below. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single PD/PI or multiple PDs/PIs. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PD/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.
Cost Sharing or Matching
This program does not require cost sharing as defined in the current NIH Grants Policy Statement.
3. Other-Special Eligibility Criteria
Renewal (formerly “competing continuation”) applications will not be accepted.
Applicants may submit more than one application, provided each application is scientifically distinct.
To download a SF424 (R&R) Application Package and
SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for
this FOA, link to http://www.grants.gov/Apply/ and follow the directions provided on that Web site.
A one-time registration is required for institutions/organizations at both:
PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.
Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:
1) Organizational/Institutional Registration in Grants.gov/Get Started
3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.
Both the PD/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.
Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.
Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.
1. Request Application Information
Applicants must download the SF424 (R&R) application forms and SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.
Note: Only the forms package
directly attached to a specific FOA can be used. You will not be able to use
any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA),
although some of the "Attachment" files may be useable for more than
For further assistance, contact GrantsInfo: Telephone 301-435-0714, Email: GrantsInfo@nih.gov.
Telecommunications for the hearing impaired: TTY 301-451-5936.
2. Content and Form of Application Submission
Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/APPLY.
The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”
The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY will include all applicable components, required and optional. A completed application in response to this FOA will include the following components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Modular Budget
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form
Foreign Organizations (Non-domestic (non-U.S.) Entity)
NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600260.
Applications from foreign organizations must:
Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.
Applications with Multiple PDs/PIs
When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact” PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.
Information for the Contact PD/PI should be entered in item 15 of the SF424(R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of “PD/PI.” Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the “Credential” field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.
All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership of the project.
Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled “Multiple PD/PI Leadership Plan” (Section 14 of the Research Plan Component in the SF424 (R&R)), must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, including communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.
If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.
Applications Involving a Single Institution
When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.
Applications Involving Multiple Institutions
When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.
When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.
Submission Dates and Times
See Section IV.3.A for details.
3.A. Submission, Review, and Anticipated Start Dates
Opening Date: February 25, 2008 (Earliest date an application may be submitted to Grants.gov) Letters of Intent Receipt Date(s): February 25, 2008
Application Submission/Receipt Date(s): March 25, 2008
Peer Review Date(s): July/August, 2008
Council Review Date(s): August2008
Earliest Anticipated Start Date(s): September 30, 2008
3.A.1. Letter of Intent
Prospective applicants are asked to submit a letter of intent that includes the following information:
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.
The letter of intent is to be sent by the date listed in Section IV.3.A.
The letter of intent should be sent to:
Abraham P. Bautista, Ph.D.
Chief, Extramural Project Review Branch
Office of Extramural Activities
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 3039
Rockville, MD 20852
Telephone: (301) 443-9737
Fax: (301) 443-6077
3.B. Submitting an Application Electronically to the NIH
To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/Apply and follow steps 1-4. Note: Applications must only be submitted electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED.
In order to expedite the review, applicants are requested to notify the NIAAA Referral Office by email firstname.lastname@example.org when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.
Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.
Upon receipt, applications will
be evaluated for completeness by the Center for Scientific Review, NIH.
Incomplete applications will not be reviewed.
There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.
Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on their application status in the Commons.
The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.
4. Intergovernmental Review
This initiative is not subject to intergovernmental review.
5. Funding Restrictions
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. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.
The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See the NIH Grants Policy Statement.
6. Other Submission Requirements
PD/PI Credential (e.g., Agency Login)
The NIH requires the PD/PI to fill in his/her Commons User ID in the “PROFILE – Project Director/Principal Investigator” section, “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component. The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see “Registration FAQs – Important Tips -- Electronic Submission of Grant Applications.”
The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”
Warning: Please be sure that you observe the direct cost, project period, and page number limitations specified above for this FOA. Application processing may be delayed or the application may be rejected if it does not comply with these requirements.
PHS398 Research Plan Component Sections
While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.
All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following requirements for R01 applications:
NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html.
Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).
Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review process.
Foreign Applications (Non-domestic (non-U.S.) Entity)
NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.
(a) Data Sharing Plan: Investigators seeking $500,000 or more in direct costs in any year are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.
(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.
(c) Genome Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. GWAS is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.
Only the review criteria described below will be
considered in the review process.
2. Review and Selection Process
Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIAAA in accordance with the review criteria stated below.
As part of the initial merit review, all applications will:
Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:
The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.
Note that an application does not need to be strong in all
categories to be judged likely to have major scientific impact and thus deserve
a high priority score. For example, an investigator may propose to carry out
important work that by its nature is not innovative but is essential to move a
Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? For applications designating multiple PDs/PIs, does the Leadership Plan ensure that there will be sufficient coordination and communication among the PDs/PIs? Are the administrative plans for the management of the research project appropriate, including plans for resolving conflicts?
Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?
Investigators: Are the PD/PI(s) and other key personnel appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the PD/PI(s) and investigative team bring complementary and integrated expertise to the project (if applicable)?
Environment: Do(es) the scientific environment(s) in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?
Additional Review Criteria:
In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:
of Human Subjects from Research Risk: The involvement of human subjects and
protections from research risk relating to their participation in the proposed
research will be assessed. See the “Human Subjects Sections” of the PHS398
Research Plan component of the SF424 (R&R).
Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. See the “Human Subjects Sections” of the PHS398 Research Plan component of the SF424 (R&R)
Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the adequacy of the plans for their care and use will be assessed. See the “Other Research Plan Sections” of the PHS398 Research Plan component of the SF424 (R&R).
Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.
2.B. Additional Review Considerations
Budget and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. The priority score should not be affected by the evaluation of the budget.
Applications from Foreign Organizations: Whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources will be assessed.2.C. Resource Sharing Plan(s)
When relevant, reviewers will be instructed to comment on the reasonableness of the following Resource Sharing Plans, or the rationale for not sharing the following types of resources. However, reviewers will not factor the proposed resource sharing plan(s) into the determination of scientific merit or priority score. Program staff within the funding organization will be responsible for monitoring the data sharing policy
Data Sharing Plan [http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm]
Sharing Model Organisms [http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html]
Genome Wide Association Studies (GWAS) [http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html]
Anticipated Announcement and Award Dates
After the peer review of the application is completed, the PD/PI will be able to access his/her Summary Statement (written critique) via the NIH eRA Commons.
If the application is under
consideration for funding, NIH will request "just-in-time"
information from the applicant. For details, applicants may refer to the NIH
Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards,
Subpart A: General.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.
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. See Section IV.5., “Funding Restrictions.”
2. Administrative and National Policy Requirements
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.
When multiple years are involved, awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.
We encourage your inquiries
concerning this funding opportunity and welcome the opportunity to answer
questions from potential applicants. Inquiries may fall into three areas: scientific/research,
peer review, and financial or grants management issues:
1. Scientific/Research Contacts:
Lindsey Grandison, Ph.D
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane
Room Number 2057
Bethesda, MD 20892-9304
Telephone: (301) 443-0606
Fax: (301) 443-1650
2. Peer Review Contacts:
Abraham P. Bautista, Ph.D.
Chief, Extramural Project Review Branch
Office of Extramural Activities
National Institute on Alcohol Abuse and Alcoholisms
5635 Fishers Lane, Room 3039
Rockville, MD 20852
Telephone: (301) 443-9373
Fax: (301) 443-6077
3. Financial or Grants Management Contacts:
Ms. Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 3023
Bethesda, MD 20892-9304
Telephone: (301) 443-4704
Fax: (301) 443-3891
Section VIII. Other Information
Required Federal Citations
Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.
Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).
Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.
Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.
NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.
NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.
For more information about the Policy or the submission process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools, including the Authors' Manual.
URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.
Authority and Regulations: This program is described in the Catalog of Federal
Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review. 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. All awards are subject to the terms and conditions,
cost principles, and other considerations described in the NIH Grants
The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
Office of Extramural
National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
Department of Health
and Human Services (HHS)
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