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 of Diabetes and Digestive and Kidney Diseases (NIDDK), (http://www.niddk.nih.gov/)
National Institute of Allergy and Infectious Diseases (NIAID), (http://www.niaid.nih.gov/)

Title: Animal Models of NIDDK-Relevant Diseases

Announcement Type
New

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

Program Announcement (PA) Number: PA-05-049

Catalog of Federal Domestic Assistance Number(s)
93.847, 93.848, 93.849, 93.855

Key Dates
Release Date: February 10, 2005
Letters of Intent Receipt Date(s): Not applicable
Application Receipt Dates(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Peer Review Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Council Review Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Earliest Anticipated Start Date: http://grants.nih.gov/grants/funding/submissionschedule.htm
Additional Information To Be Available Date (Url Activation Date): Not applicable
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
      A. Cooperative Agreement Terms and Conditions of Award
        1. Principal Investigator Rights and Responsibilities
        2. NIH Responsibilities
        3. Collaborative Responsibilities
        4. Arbitration Process
    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

The purpose of this Program Announcement is to encourage the development and validation of new animal models of NIDDK-relevant diseases. Of interest are projects that will generate models in diseases where existing animal models are either inadequate or lacking. It is anticipated that new disease models developed under this initiative will facilitate testing of emerging diagnostic, preventive and therapeutic interventions, leading to better treatments and cures for diseases within the mission of the NIDDK.

The ability to translate basic findings into disease cures often relies on animal models that serve as surrogates of the human condition. Many diseases relevant to the NIDDK mission lack validated animal models, hampering translational progress in several important disease areas. In some cases, animal models of the disease have yet to be identified. New and/or improved models can often be developed by recapitulating mutations associated with human genetic susceptibility loci, by altering biologic pathways known or suspected to be involved in human diseases, by screening for phenotypes related to those associated with human diseases in spontaneous or induced mutant animals, and/or by monitoring phenotypes in animal models that are induced through pharmacologic, dietary or environmental factors. Success is dependent on having a clear definition of the human disease or disease aspect to be modeled, and on having established criteria for validating the model as a correlate of human disease.

NIAID is also participating in this initiative, and has an interest in models designed to test interventions directed toward immune mechanisms underlying several NIDDK-relevant diseases, including Type 1 diabetes, autoimmune liver diseases, allergic drug-induced liver injury, and celiac disease.

Examples of areas within the mission of NIDDK where new and/or improved validated animal models are particularly encouraged include, but are not limited to:

Type 1 Diabetes (T1D)

Type 1 diabetes in rodents and humans is a complex disease that is dependent on multiple genetic interactions and environmental influences. Existing animal models of T1D have been powerful tools for identifying and characterizing these interactions at the cellular and molecular level. Studies in animals have shown that passage through multiple biologic checkpoints is required for T1D progression, and that phenotypes associated with these checkpoints are similar to risk factors identified in human disease. Several approaches have been taken to obtain rodent models of T1D, including introducing specific mutations that affect the initiation or regulation of immune responses, or that affect beta cell growth and viability. New T1D strains are also being identified through genetic screening of induced or natural mutants, or by recombining subsets of genetic polymorphisms associated with diabetes into disparate mouse backgrounds. Nevertheless, given the striking level of genotypic and phenotypic concordance between mouse and human T1D, therapeutic success in rodents has not been highly predictive of therapeutic success in humans. This growing experience with rodent models highlights the need to identify new animal models of T1D that may more accurately predict the efficacy of therapeutics in humans.

Cystic Fibrosis

Cystic Fibrosis (CF) is one of the most common lethal autosomal disorders in the US. Mutations in CF alter the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), a major cAMP-regulated chloride channel. To date, no fewer than ten mouse models have been generated that mimic CFTR gene mutations found in human disease. However, none of these mutant mouse strains model all clinical manifestations of CF. While the intestinal pathophysiology of human CF is observed in mouse models, the pulmonary changes responsible for 95% of the morbidity and mortality of human CF are not observed. This lack of correlation between murine and human CF phenotypes limits the utility of existing mouse models for testing new therapies for cystic fibrosis. New ideas and innovative approaches will be needed to provide fully realized animal models of CF. These could include using different species which more closely reflect the pulmonary physiology of humans, or rodents bearing defined combinations of mutations in CF modifier genes.

Diseases of the Liver and Biliary Tract

Chronic liver diseases from a variety of etiologies eventually progress to liver cirrhosis, present clinically as end stage liver disease, and require liver transplantation to extend life. Most therapies designed to avert end stage liver disease are not curative, and a search for new and improved therapies remains a high priority. Progress in identifying new therapeutics for these diseases has been hampered by a lack of accurate animal models for testing reagents. For these reasons, development of animal models for chronic liver diseases is considered a high priority research goal specified in the NIDDK Liver Diseases Research Action Plan (http://liverplan.niddk.nih.gov).

Mouse models of autoimmune liver diseases reflect only acute injury, and rely on changes in one or a few pathways of cell damage to model the condition. New animal models that reflect chronic features of these disorders, including chronic necroinflammation and fibrosis would be most useful. Similarly, several animal models of fatty liver disease exist, including models of nonalcoholic fatty liver diseases. However, none of these models accurately reflect the pattern and progression of cell injury, inflammation and fibrosis needed to screen and test new therapeutics directed at nonalcoholic steatohepatitis (NASH). In addition, while knowledge of the genes associated with inherited diseases has led to advances in understanding disease pathophysiology, this information has not translated into advances in diagnosis or therapy for many major forms of genetic liver diseases, as well as cholestatic liver disease. Animal models that would enable testing of new therapeutics for these conditions are badly needed.

At present there are no reliable animal models for allergic or non-allergic drug-induced liver injury. Models capable of predicting medication-induced hepatotoxicity are needed to facilitate progress toward enhanced prediction, early diagnosis, management and treatment of drug-induced liver diseases. Adaptation to liver injury during chronic administration of a medication also occurs frequently in humans, and failure of this adaptation is a potential mechanism for the uncommon acute liver injury initiated by medications. An animal model that would accurately reflect the process of liver adaptation as it occurs during treatment with a hepatotoxic drug would provide an important advance toward identifying therapies to prevent or ameliorate drug-induced liver injury.

Finally, animal models of monogenic inherited diseases of the liver usually rely on deletion (knock out) of a specific gene or transgenic expression of an abnormal gene (knock in) in a mouse model. Knock-out or –in models for several diseases have been produced that accurately reflect the genetic defect, but these models fail to recapitulate the human disease. Thus, animal models of cystic fibrosis and Byler's disease are not associated with liver disease that resembles the human condition. Animal models designed to more closely reflect the human condition through incorporation of appropriate modifier genes are needed to promote rapid progress toward new and innovative therapies for these diseases.

Diseases of the Pancreas and Digestive Tract

Acute pancreatitis is a prevalent disease of the pancreas with considerable morbidity and mortality. Chronic pancreatitis results from recurrent episodes of acute pancreatitis and could lead to pancreatic insufficiency with resulting nutrient malabsorption, diabetes mellitus and chronic abdominal pain.

While autolysis of the pancreatic acini is a common pathogenic step in acute pancreatitis, multiple etiologies have been identified: gallstones, alcohol, infections, drugs, hyperlipidemia, trauma and hereditary factors. The pathogenesis of this disease is incompletely understood due to the difficulty in obtaining clinical specimens, and due to a lack of animal models that recapitulate the natural history of the human disease with its differing etiologies. New animal models designed to reproduce both acute and chronic pancreatitis are clearly needed to advance our understanding of the pathophysiology and to facilitate testing of diagnostic, preventive or therapeutic interventions for these conditions and their complications.

Barrett's esophagus is a condition in which the normal lining of the esophagus, stratified squamous epithelium, is replaced by columnar epithelium. It develops as a complication of chronic gastroesophageal reflux in 10 -12 % of patients and predisposes to the development of adenocarcinoma. Over the last two decades the incidence of adenocarcinoma has been increasing more rapidly than that of any other cancer. This finding lends a new urgency to the search for animal models of Barrett's esophagus that could aid in the search for therapies for this condition.

A number of motility disorders of the gastrointestinal tract continue to present therapeutic challenges. New animal models are needed for Hirschsprung's disease, a developmental abnormality of the colon that causes delayed passage of meconium and abdominal distension in newborns, as well as chronic constipation, distension and colonic perforation in older children. Validated models are also lacking for Achalasia, where a disruption of neuromuscular control of the esophagus results in dysphagia. Other conditions associated with altered intestinal motility that requires validated animal models include chronic pseudo-obstruction and intestinal neuronal dysplasia. In all of these cases, animals that accurately model the disease conditions are urgently needed to enhance development of diagnostic, preventive and therapeutic interventions.

Gastroparesis is a disorder of the stomach characterized by delayed gastric emptying without evidence of obstruction. The majority of gastroparesis patients are middle-aged women (82%) with symptoms that include nausea, vomiting, bloating, early satiety, and abdominal pain/discomfort. The primary causes of gastroparesis are idiopathic (36%), although diabetic and post-surgical gastroparesis comprise 42% of patients affected by the disorder. Parkinson's disease, collagen vascular disorders, and intestinal pseudo-obstruction are rarer causes. Studies funded under this PA would support the development of animal models designed to test new therapies for this significant cause of morbidity in adults.

Irritable bowel syndrome (IBS) continues to pose a challenge for the clinician. IBS is characterized by abdominal pain which is associated with defecation or a change in bowel habit or disordered defecation. Research over the last decade has shown that visceral hypersensitivity and stress is characteristic of IBS. Although progress has been made in understanding the pathophysiology of this disorder, validated animal models of the condition are needed to provide appropriate test systems for newly emerging therapies.

Celiac disease is an immune-mediated disorder that affects primarily the gastrointestinal tract. It is characterized by chronic inflammation of the small intestinal mucosa that may result in atrophy of intestinal villi, malabsorption, and a variety of clinical manifestations, which may begin in either childhood or adult life. Considerable progress has been made in understanding celiac disease and in preventing or curing its manifestations by dietary interventions. However, the development of animal model(s) of celiac disease would greatly enhance our understanding of the pathogenic mechanisms involved in this disease with a genetic predisposition.

Models of Kidney, Urologic and Hematologic Diseases

The greater scientific community lacks animal models that closely mimic a number of NIDDK-relevant diseases affecting the kidney, bladder and hematologic systems. This PA aims to support the creation of new animal models for these diseases and thus facilitate the development of diagnostic and therapeutic interventions. Particularly encouraged are novel animal models for primary diseases of the kidney such as acute renal failure, autoimmune kidney disease, glomerular and tubulointerstitial disease, nephrolithiasis, uremic complications of renal failure and vascular complications of hemodialysis access. New and continued efforts are also encouraged for generating faithful animal models of bladder disorders such as reflux and incomplete emptying, and hematologic disorders such as the thalassemias, hemochromatosis and iron overload.

Diabetic Complications

Much of the morbidity and mortality associated with diabetes can be attributed to complications of the disease affecting a variety of organs, including NIDDK-relevant organs. To enhance translational efforts for these conditions, this PA encourages the development and validation of new animal models of diabetic complications, especially those affecting NIDDK-specific organ systems (including diabetic nephropathy, uropathy, and gastropathy). The NIDDK-supported Animal Models of Diabetic Complications Consortium (AMDCC; www.amdcc.org) has played a leadership role in establishing standard assays and diagnostic criteria for diabetic complications in animals. While progress has been made through the AMDCC effort, establishing new validated animal models of human diabetic complications remains a high priority for NIDDK. Such models are critical for identifying and testing diagnostic, preventive, or therapeutic interventions for these devastating conditions.

2. Research Topics

The objective of the Program Announcement is to support studies that will identify, develop, and verify the utility of new animal models for use in preclinical studies of NIDDK-relevant diseases. It is anticipated that new and/or improved animal models will stimulate rapid progress in translational research for many diseases within the NIDDK mission. Animal models of NIDDK-relevant diseases to be supported under this Program Announcement may include, but are not limited to:

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the NIH investigator-initiated Research Project Grant (R01) 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. Consortium/contractual F&A costs may be requested in addition to the $250,000 and the modular budget would still be used. Otherwise, follow the instructions for non-modular research grant applications.

2. Funds Available

The NIDDK intends to fund up to 5-6 new grants per year in response to this Program Announcement. The budget request should be tailored to meet the needs of your project.

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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-05-004.html.

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 or Matching is not required.

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

3. Other-Special Eligibility Criteria
Investigators may submit more than one application for this PA, provided there is no scientific or budgetary overlap.

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.

3. Submission Dates and Times
Applications must be mailed on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: Not required.
Application Receipt Date(s): http://grants.nih.gov/grants/funding/submissionschedule.htm
Peer Review Date: http://grants.nih.gov/grants/funding/submissionschedule.htm
Council Review Date: http://grants.nih.gov/grants/funding/submissionschedule.htm
Earliest Anticipated Start Date: http://grants.nih.gov/grants/funding/submissionschedule.htm

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 PHS 398 research grant application instructions and forms as described above. 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)

3.C. Application Processing

Applications must be submitted on or before the application receipt 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.

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. 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 (see also Section VI.3. Reporting).

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/archive/grants/policy/nihgps_2003/index.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.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

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.

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/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.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.

1. 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?

2. 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?

3. 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?

4. 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)?

5. 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.

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/archive/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/archive/grants/policy/nihgps_2003/index.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.

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.

The NGA will be sent by email to the Business Official with a copy to the Principal Investigator.

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/archive/grants/policy/nihgps_2003/index.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/archive/grants/policy/nihgps_2003/index.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award
Not applicable

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:

Kristin M. Abraham, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 607
Bethesda, MD 20892-5460
Telephone: (301) 451-8048
FAX: (301) 480-3503
Email : ka136s@nih.gov

Christian J. Ketchum, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 647
Bethesda, MD 20892-5458
Telephone: (301) 596-7717
FAX: (301) 480-3510
Email : ck228s@nih.gov

Robert W. Karp, Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 671
Bethesda, MD 20892-5450
Telephone: (301) 451-8875
FAX: (301) 480-8300
Email : rk56v@nih.gov

Annette L. Rothermel, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6610 Rockledge Drive, Room 3020
Bethesda, MD 20892-6601
Telephone: (301) 496-7104
FAX: (301) 480-1450
Email : ar299e@nih.gov

2. Peer Review Contacts:
Not applicable

3. Financial or Grants Management Contacts:

Randi Freundlich, R.D.
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 724
Bethesda, MD 20892-5456
Telephone: (301) 594-8825
FAX: (301) 480-3504
E-mail: rf160d@nih.gov

Ann White-Devine
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 2118
Bethesda, MD 20892-7614
Telephone: (301) 402-5601
FAX: (301) 480-3780
E-mail: ad22x@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/archive/archive/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.

Public 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 public 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 PA 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.


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