Part I Overview Information

Department of Health and Human Services

Participating Organizations
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)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), (http://www.niddk.nih.gov)
Office of Dietary Supplements (ODS), (http://www.ods.od.nih.gov)

Title: Mechanisms of Alcoholic and Nonalcoholic Fatty Liver (Steatosis)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

Program Announcement (PA) Number: PA-05-119

Catalog of Federal Domestic Assistance Number(s)
93.273, 93.848

Key Dates
Release Date: June 10, 2005
Letters of Intent Receipt Date(s): Not applicable
Application Submission Dates(s): Standard dates apply, please use http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Peer Review Date(s): Standard dates apply, please use http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Council Review Date(s): Standard dates apply, please use http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Earliest Anticipated Start Date: Standard dates apply, please use http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Additional Information To Be Available Date (Url Activation Date):
Expiration Date for R03 and R21 Non-AIDS Applications: March 2, 2006
Expiration Date for R03 and R21 AIDS and AIDS-Related Applications: May 2, 2006
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

 Section I. Funding Opportunity Description
   1. Research Objectives

 Section II. Award Information
   1. Mechanism(s) of Support
   2. Funds Available

 Section III. Eligibility Information
   1. Eligible Applicants
     A. Eligible Institutions
     B. Eligible Individuals
   2.Cost Sharing or Matching
   3. Other - Special Eligibility Criteria

 Section IV. Application and Submission Information
   1. Address to Request Application Information
   2. Content and Form of Application Submission
   3. Submission Dates and Times
     A. Receipt and Review and Anticipated Start Dates
       1. Letter of Intent
     B. Sending an Application to the NIH
     C. Application Processing
   4. Intergovernmental Review
   5. Funding Restrictions
   6. Other Submission Requirements

 Section V. Application Review Information
   1. Criteria
   2. Review and Selection Process
     A. Additional Review Criteria
     B. Additional Review Considerations
     C. Sharing Research Data
     D. Sharing Research Resources
   3. Anticipated Announcement and Award Dates

 Section VI. Award Administration Information
   1. Award Notices
   2. Administrative and National Policy Requirements
   3. Reporting

 Section VII. Agency Contact(s)
   1. Scientific/Research Contact(s)
   2. Peer Review Contact(s)
   3. Financial/ Grants Management Contact(s)

 Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement
Section I. Funding Opportunity Description

1. Research Objectives

Background

Alcoholic Liver Disease (ALD) and Nonalcoholic Fatty Liver Disease (NAFLD) are major cause of illness and death in the United States. In the initial stage of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis) which is characterized by an excess triglyceride deposition. NAFLD is often associated with elements of the metabolic syndrome, a clinical constellation of obesity, hypertension, insulin resistance, glucose intolerance and hyperlipidemia and encompasses a spectrum of liver disorders from the simple hepatic steatosis to the more ominous condition known as nonalcoholic steatohepatitis (NASH). Several mechanisms that underlie the accumulation of liver steatosis in association with obesity and the metabolic syndrome appear to be in common with alcoholic fatty liver. Thus, if alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may eventually lead to liver cirrhosis. Similarly, steatosis in NAFLD may ultimately lead to clinically significant progressive liver injury, fibrosis and cirrhosis. Simple fatty liver has long been considered benign; however, increasing evidence suggests that it is a potentially pathologic condition and precedes the development of alcoholic or nonalcoholic steatohepatitis and cirrhosis. In alcoholic liver disease, this assumption is based on features reported to be associated with fatty liver developed as a result of chronic administration of Lieber-DeCarli liquid diet (36% alcohol calories) to rats including: 1) induction of hepatic cytochrome P4502E1 (CYP2E1); 2) increased hepatic levels of 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation; 3) increased deposition of iron in the liver; 4) selective hepatic mitochondrial glutathione (GSH) reduction and mitochondrial dysfunction; 5) hepatic S-adenosylmethionine (SAMe) reduction; 6) increased concentration of serum tumor necrosis factor-alpha (TNF-á) and increased hepatic expression of TNF-á mRNA levels; 7) elevated serum alanine aminotransferase (ALT) levels; and 8) increased hepatic levels of cellular fibronectin and alpha smooth muscle actin (á-SMA). Many of these factors may also play a role in the evolution of fatty liver of NAFLD to nonalcoholic steatohepatitis, providing the so-called “second hit” involved in the pathogenesis of NASH.

Induction of CYP2E1 activity, increased levels of 4-HNE, increased deposition of iron, and depletion of SAMe and GSH are markers of oxidative stress, which is known to play a pivotal role in the pathogenesis of steatosis to the more severe liver disorders, NASH and ALD. TNF-á has been implicated in the pathogenesis of alcoholic and nonalcoholic fatty liver injury in humans as well as in animals. An increased level of serum alanine aminotransferase ( ALT) is a marker of hepatic injury. Increased level of hepatic cellular fibronectin is an early response to liver injury, and increased levels of á-SMA suggest stellate cell activation, which may result in excess of collagen deposition and subsequent fibrosis. These findings clearly suggest that fatty liver is a potential pathologic condition and that accumulated fat can sensitize liver to further injury such as inflammation, fibrosis, and cirrhosis.

Preventing the accumulation of fat within liver or degradation of accumulated fat may block or delay the progression of fatty liver to steatohepatitis and fibrosis. In order to achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms which lead to fat accumulation in the liver due to alcohol consumption as well as metabolic factors such as obesity and insulin resistance. Excess fat accumulation in the liver could result from increased transportation of fatty acids from the peripheral organs to the liver, increased hepatic fatty acid synthesis, impaired hepatic fatty acid oxidation, increased triglyceride synthesis in the liver, and/or diminished export of triglycerides from the liver.

Scope of Research

The purpose of this PA is to encourage research grant applications that will use an integrative approach of state-of-the-art technologies to gain insight into the molecular mechanisms of both alcoholic and nonalcoholic fatty liver. This includes investigating the mechanisms by which alcohol and nonalcoholic metabolic factors: a) accelerate import of free fatty acids into hepatocytes; b) impair mitochondrial â-oxidation of fatty acids; c) impede the entry of free fatty acids into mitochondria; d) promote de novo fatty acid synthesis; e) promote esterification of free fatty acids into triglycerides; and f) disrupt export of triglycerides from hepatocytes through very low density lipoprotein (VLDL).

NIAAA, NIDDK, and ODS also encourage research to develop non-invasive biomarkers for fatty liver, using genomic, proteomic, and metabolomic technologies. Proposals investigating the modulating effects of dietary fatty acids, obesity, diabetes, and insulin resistance on the development of alcoholic and nonalcoholic fatty liver are also encouraged.

a. Increased Hepatic Uptake of Fatty Acids :

Fatty acid levels are significantly increased in the liver after alcohol consumption and in persons with obesity and the metabolic syndrome. Alcohol may increase hepatic fatty acid uptake by increasing hepatic blood flow. In addition, studies with isolated hepatocytes and perfused livers have suggested that alcohol can directly increase fatty acid uptake independent of blood flow. This could be due to a direct effect of alcohol on the physical properties of the hepatic plasma membrane consequent to altered lipid composition. Further studies are required to delineate the role of fatty acids and the modulatory effect of alcohol and the metabolic syndrome upon hepatic uptake of fatty acids.

b. Impaired Fatty Acid Oxidation:

Alcohol and excess fatty acids have been shown to inhibit fatty acid oxidation in liver slices from rats and humans, in perfused rat liver, in rat hepatocytes, and in vivo in humans. Various mechanisms have been proposed for this effect. A redox shift resulting in increased ratio of NADH/NAD+ has been implicated in the development of fatty liver via inhibition of mitochondrial fatty acid beta oxidation and tricarboxylic acid cycle. However, normalization of redox state failed to attenuate alcohol-induced fatty liver, suggesting that other mechanisms may also be contributing to this condition.

Alcohol and excess fatty acids may also impair fatty acid oxidation by inhibiting the activities of enzymes involved in fatty acid oxidation. Peroxisome proliferators-activated receptor alpha (PPAR-á) is a member of the nuclear hormone receptor super family, which when dimerized with retinoid X receptor alpha (RXR-á) regulates transcription of a set of genes involved in the oxidation and transport of fatty acids. Chronic ethanol feeding has been shown to decrease RXR-á protein levels, inhibit DNA binding of the PPAR-á/RXR-á heterodimer, and decrease the levels of mRNA for several PPAR-á regulated genes in the liver of mice. These findings were associated with the development of fatty liver. Simultaneous administration of a PPAR-á agonist attenuated some of these effects, including progression of fatty liver, despite continued ethanol administration. These results suggest that chronic ethanol may inhibit fatty acid oxidation by inhibiting PPAR-á activity via decreasing RXR-á protein levels and subsequently impairing DNA binding of PPAR-á/RXR-á heterodimer. However, mechanisms by which chronic ethanol decreases RXR-á levels are not clear. Furthermore, the significance of RXR-á levels in the DNA binding of PPAR-á/RXR-á is not clear since treatment of ethanol-treated animals with PPAR-á agonist restored DNA binding ability without increasing RXR-á levels. Further research is required to investigate various fatty acid oxidation pathways that are impaired by excess fatty acids and by ethanol consumption.

c. Impaired Transport of Fatty Acids into Mitochondria:

Transport of free fatty acids from cytosol to mitochondria is a required for mitochondrial beta oxidation of fatty acids. This transport is accomplished primarily through an enzyme, carnitine palmitoyltransferase-1 (CPT-1) located at the outer membrane of mitochondria. Chronic ethanol has been shown to reduce the activity of CPT-1, which may impair the transport of fatty acids into mitochondria that in turn may result in reduced fatty acid oxidation. Ethanol may inhibit CPT-1 activity by triggering a cascade of events starting from an activation of sterol regulatory element-binding protein (SREBP) to up-regulation of acetyl Co-A carboxylase (ACC), and subsequent increased production of malonyl Co-A that is known to inhibit CPT-1 activity. Alternatively, ethanol may inhibit CPT-1 activity by triggering another cascade of events starting from inhibition of PPAR-á activity to inhibition of malonyl Co-A decarboxylase (MCD) activity, and subsequent increased production of malonyl Co-A.

d. Accelerated de novo Fatty Acid Synthesis:

Chronic ethanol use and metabolic stresses such as obesity and insulin resistance have been shown to stimulate lipogenesis in the liver through increased transcription of genes for lipogenic enzymes. The SREBPs are a family of transcription factors that are key regulators for cholesterol and fatty acid synthesis; they exert their effect by directly activating the expression of more than 30 genes in the liver. Recently, researchers have demonstrated that chronic ethanol administration can significantly increase the production of hepatic SREBP-1, which is associated with increased expression of lipogenic genes as well as accumulation of triglycerides in the liver. Using 4-methylpyrazole and cyanamide, it was shown that this effect of alcohol was dependent on its metabolism to acetaldehyde. Alcohol-induced lipogenesis appears to be modulated by the dietary concentration of carbohydrate and fat. While higher carbohydrate and low fat diet may promote lipogenesis by providing excess pyruvate for the synthesis of acetyl-CoA (precursor for fatty acid synthesis), higher fatty acid and low carbohydrate diet may inhibit lipogenesis by inhibiting the activities of lipogenic enzymes. Further studies are required to understand the role of SREBPs in hepatic fatty acid synthesis in human alcoholics administered with variable concentrations of fat and carbohydrate in their diet. In addition, role of acetate in the synthesis of fatty acids via acetyl Co-A needs to be evaluated.

e. Increased Esterification of Free Fatty Acids into Triglycerides:

The increased supply of free fatty acids in the liver of alcoholics and persons with obesity, insulin resistance and the metabolic syndrome along with reduced ability of liver to oxidize these compounds can lead to their esterification and storage as triglycerides, resulting in fatty liver. Several animal studies suggest that alcohol intake can increase esterification of free fatty acids into triglycerides. This is primarily due to ethanol-induced up-regulation of phosphatidate phosphohydrolase (PAP), the rate limiting enzyme in triglyceride synthesis. Both acute and chronic alcohol administration have been shown to up-regulate hepatic PAP activity in rats, hamsters, and baboons. However, the mechanisms of this effect of ethanol are not clear. Studies are required to understand the relative role of PAP in the development of alcoholic fatty liver. Whether ethanol affects other enzymes of esterification pathway needs investigation.

f. Decreased Export of Triglycerides from the Liver:

Triglycerides are generally exported from the liver by very low-density lipoproteins (VLDL) particles, which are assembled through a complex process and made of triglycerides, cholesterol, phosphatidylcholine, and apolipoproteins. Inhibition of this process at any of several levels may result in accumulation of triglycerides in hepatocytes and consequently development of fatty liver. Studies with perfused livers, isolated hepatocytes, and alcohol fed rats have shown that alcohol can inhibit secretion of VLDL and this may contribute to the development of fatty liver. Alcohol's metabolite acetaldehyde may impair VLDL secretion by reacting with lysine residue of tubulin (a cytoskeleton protein), resulting in acetaldehyde-tubulin adduct formation. This may impair microtubule formation and consequently VLDL secretion. Alcohol may also impair triglyceride export by inhibiting the synthesis of phosphatidylcholine (via inactivating phosphatidylethanolamine methyl transferase activity), which is an important component of VLDL formation. In addition, alcohol may impair transport by inhibiting apolipoprotein synthesis through inhibition of PPAR-á activity. Studies are required to understand the mechanisms which impair the formation, intracellular transport through the cytoskeleton, and secretion of VLDL.

g. Role of Dietary Fatty Acids:

Dietary fat has been shown to play an important role in the development of steatosis and in the pathogenesis of ALD. While polyunsaturated fatty acids potentiate the severity of alcoholic liver injury, saturated fatty acids are protective. On the other hand, phospholipids such as phosphatidylcholine (soybean extract) have been shown to prevent alcohol-induced fibrosis and cirrhosis in baboons. The toxic effects of polyunsaturated fatty acids are thought to be mediated through increased oxidative stress (lipid peroxidation), whereas the mechanisms of the protective effects of saturated fatty acids and phospholipids are not clear. Understanding the underlying molecular mechanisms by which different types of fats potentiate or prevent hepatic steatosis may help to develop dietary interventions for the prevention or treatment of the disease.

h. Modifying Factors:

The metabolic syndrome components individually or collectively may modulate the course of alcoholic fatty liver and vice versa. Heavy alcohol consumption is associated with insulin resistance and increased plasma levels of insulin, which is known to accelerate de novo fatty acid synthesis in the liver. Alcohol consumption has been reported to promote obesity in some individuals, and obesity has been reported to increase the risk of fatty liver, hepatitis, and cirrhosis caused by chronic alcohol consumption. Likewise, individuals with the metabolic syndrome may sensitize to the steatotic effects of alcohol. In cross sectional studies of the U.S. population, alcohol consumption was associated with a higher rate of liver enzyme abnormalities largely among persons who were overweight or obese. The combined effect of obesity and alcohol consumption on the development of hepatic steatosis needs further elucidation.

i. Biomarkers of Alcoholic Fatty Liver:

There are about 8 million people with alcoholism in the USA, who may be affected with fatty liver. If these people continue drinking, at least 20% of them are likely to develop hepatitis and/or cirrhosis. In addition, there are about 42 million obese individuals who may also be affected with fatty liver. Among individuals who progress from steatosis to NASH, approximately 15% will develop cirrhosis. Therefore it is important to be able to identify individuals with fatty liver for intervention before this condition progresses to hepatitis or cirrhosis. Ultrasound is a very sensitive method for detecting fatty liver, but it is not specific for this condition and the procedure is costly. An AST:ALT ratio of >2 is considered by some investigators specific for alcoholic fatty liver; however, other investigators have not confirmed this finding. Studies are required to develop specific and sensitive non-invasive biomarkers – utilizing blood, urine, saliva, or hair – for the diagnosis of fatty liver. Advanced techniques such as genomics, proteomics, and metabolomics are encouraged for these studies.

j. Use of Novel Approaches:

Recent advances in functional genomics, both conceptually and technologically, are providing us tremendous opportunities to decipher the interconnecting networks of genes, proteins, and metabolites. These global approaches can be generally carried out at four major levels: genome, transcriptome, proteome, and metabolome. The studies at genome level include sequencing, polymorphism (such as SNP), haplotype, genetic variation, QTL, genetic or epigenetic alterations. The studies at transciptome level include gene expression profiling (by DNA microarray, SAGE, RAGE, or other types of techniques), gene regulation, and alternative splicing. The studies at proteome level are to use systematic approaches to study proteins for their identity, quantity, and function. At metabolome level, metabolomics involves a detailed, quantitative analysis of low molecular weight metabolite over changing environmental conditions (e.g., alcohol administration or increasing levels of obesity ) in a biological system (human patients or animal models). The determination of these metabolites can be achieved by using spectroscopic methods, most powerfully, mass spec, NMR, and HPLC. Metabolomics can be used to identify metabolite differences associated with alcohol or alcohol-related illnesses, to discover biomarkers for diagnosis or efficacy, to identify drug targets, to determine the safety of drugs, and so on. This metabolomic information can be integrated with genome, transcriptome, and proteome information to understand the mechanisms and provide new avenues for therapeutic treatments of fatty liver. To understand how fatty liver is developed, novel approaches using advanced technologies in the areas of genomics and functional genomics are strongly encouraged. Other novel approaches such as transgenic and knockout mouse models or RNA interference are also encouraged if a gene or genes are found to play a potential role in the development of alcoholic or nonalcoholic fatty liver.

k. Areas of Research

Applications should focus on research that may contribute to understanding the role of alcohol and its metabolites acetaldehyde and acetate and nonalcoholic mechanisms in the development of fatty liver. Examples of research that might be supported under this PA include, but are not limited to, the following:

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the NIH Research Project Grant (R01), the Small Grant (R03) (see: http://grants.nih.gov/grants/guide/pa-files/PA-03-108.html), and the Exploratory/Developmental Grant (R21) (see: http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) award mechanism(s).

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses just-in-time concepts. It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions. Otherwise follow the instructions for non-modular research grant applications.

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 IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your 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 is invited to work with their institution 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 programs.

2. Cost Sharing or Matching

Cost sharing is not required

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria
Not applicable

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. 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

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide a unique research opportunity not available in the U.S.

3. Submission Dates and Times
See Section IV.3.C for details.

3.A. Submission, Review and Anticipated Start Dates

Letter of Intent Submission Date: Not applicable
Application Submission Date(s): Standard dates apply, please use http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Peer Review Date: Standard dates apply, please use http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Council Review Date: Standard dates apply, please use http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Earliest Anticipated Start Date: Standard dates apply, please use http://grants.nih.gov/grants/funding/submissionschedule.htm for details

3.A.1. Letter of Intent
A letter of intent is not required for the funding opportunity.

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant application forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

3.C. Application Processing

Applications must be submitted on or before the application receipt/submission dates described above (Section IV.3.A.) and at http://grants.nih.gov/grants/dates.htm.

Upon receipt applications will be evaluated for completeness by CSR. Incomplete applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

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. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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 or competing continuation 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 or competing continuation 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 NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Specific Instructions for Modular Grant applications

Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget format. The modular budget format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular budgets. Applicants must use the currently approved version of the PHS 398. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year.

Applicants requesting $500,000 or more in direct costs for any year must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study;

2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and,

3) Include a cover letter with the application that identifies the staff member and IC who agreed to accept assignment of the application.

This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria
Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications submitted for this funding opportunity will be assigned to the ICs on the basis of established PHS referral guidelines.

Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit.

As part of the initial merit review, all applications will:

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 field forward.

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?

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 investigators 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 investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment 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?

2.A. 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:

Protection 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 Research Plan, Section E on Human Subjects in the PHS Form 398).

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 Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

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: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the Notice of Grant Award will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the Notice of Grant Award will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also 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 notice of grant award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

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:

Vishnudutt Purohit, Ph. D.
Program Director
Division of Metabolism and Health Effects
National Institute on Alcohol Abuse and Alcoholism/NIH
5635 Fishers Lane, Room 2035, MSC 9304
Bethesda, MD 20892 -9304
Telephone: (301) 443-2689
Fax: (301) 594-0673
Email: vpurohit@mail.nih.gov

Edward Doo, M.D.
Program Officer
Liver Diseases Research Branch
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 651, MSC 5450
Bethesda, MD 20892-5450
Telephone: (301) 451-4524
Fax: (301) 480-8300
Email: DooE@niddk.nih.gov

Rebecca B. Costello, Ph.D., F.A.C.N.
Deputy Director
Office of Dietary Supplements
National Institutes of Health
6100 Executive Blvd., Room 3B01, MSC 7517
Bethesda, Maryland 20892-7517
Telephone: (301) 435-2920
Fax: (301) 480-1845
Email: CostellB@od.nih.gov

2. Peer Review Contacts:
Not applicable

3. Financial or Grants Management Contacts:

Judy S. Fox
Chief, Grants Management Branch
Chief Grants Management Officer
National Institute on Alcohol Abuse and Alcoholism/NIH
5635 Fishers Lane, Room 3023, MSC 9304
Bethesda, MD 20892-9304
Phone: 301-443-4704
FAX: 301-443-3891
Email: jfox@mail.nih.gov

Ms. Trude W. Hilliard
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 717
Bethesda, MD 20892-5450
(for FedEx, UPS use 20817)
Phone: (301) 594-8859
Fax: (301) 480-3504
Email: hilliardt@extra.niddk.nih.gov

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.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

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 http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, 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.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

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 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 Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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


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