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
Office of Research on Women's Health (ORWH), (http://www4.od.nih.gov/orwh/)
Office of Behavioral and Social Science Research (OBSSR), (http://obssr.od.nih.gov/)
National Institute on Alcohol Abuse and Alcoholism (NIAAA), (http://www.niaaa.nih.gov/)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), (http://www.niams.nih.gov/)
National Institute of Environmental Health Sciences (NIEHS), (http://www.niehs.nih.gov/)
National Institute of Neurological Disorders and Stroke (NINDS), (http://www.ninds.nih.gov/)

Title: Neuroimmune Mechanisms and Chronic Fatigue Syndrome

Announcement Type
New

Request for Applications (RFA) Number: RFA-OD-06-002

Catalog of Federal Domestic Assistance Number(s)
93.273, 93.846, 93.113, 93.114, 93.115, 93.853

Key Dates
Release Date: July 14, 2005
Letters of Intent Receipt Date(s): August 19, 2005
Application Receipt Dates(s): September 19, 2005
Peer Review Date(s): January/February, 2006
Council Review Date(s): May, 2006
Earliest Anticipated Start Date: July, 2006
Additional Information to Be Available Date (Url Activation Date): N/A
Expiration Date: September 20, 2005

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The goal of this Request for Applications (RFA) from the Office of Research on Women's Health (ORWH) and cosponsoring Institutes and Offices (IC) of the National Institutes of Health (NIH) is to solicit applications that support research on the neuroimmune mechanisms involved in the pathogenesis and pathophysiology of Chronic Fatigue Syndrome (CFS) and spectrum disorders in diverse groups and across the life span. Applications are encouraged from individuals who are part of multidisciplinary teams of scientists studying different aspects of CFS and its spectrum disorders. Chronic Fatigue Syndrome may be linked to dysregulation of at least two physiologic systems important for the maintenance of homeostasis: the central nervous system (CNS) (including the autonomic sympathetic system and the hypothalamic-pituitary-adrenal axis [HPA]) and the immune system. Several mediators may contribute to dysregulation, including activated immune cells, hormones, neurotransmitters, and others. Stress affects the activities of many of these mediators. Physiologic functions altered by stress and the ability to respond to stress likely play a role in the clinical manifestations of CFS. A variety of internal and external stressors lead to altered signaling in the central nervous and the immune systems. Whereas these changes are likely to contribute to or trigger disease symptomotology, they may obscure the original stressor initiating the event.

Research at a systems level is needed to develop an understanding of the potential interactions of neural and immune systems in the disease process and to determine how alterations in integrated physiological systems affect the progression and nature of CFS. The NIH is soliciting applications that 1) examine mediators influencing central control mechanisms and communication among interacting components of the nervous and immune systems 2) apply new tools to explore different aspects of the disease process, 3) elucidate the development of influences that may enhance disease susceptibility and contribute to mechanistic aspects of this disease and 4) identify predictive biomarkers for CFS and/or spectrum disorders. The NIH is interested in funding research that will improve the diagnosis, treatment and quality of life of all persons with this disease, using the focus developed at the NIH sponsored CFS science workshop held in June 2003 “ Neuroimmune Mechanisms and Chronic fatigue Syndrome: Will Understanding Central Mechanisms Enhance the Search for Causes, Consequences, and Treatment of CFS?” This workshop summary is found at http://www4.od.nih.gov/orwh/CFS-newhome.html.

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, 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

 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

The goal of this Request for Applications (RFA) from the Office of Research on Women's Health (ORWH) and cosponsoring Institutes and Offices (ICs) of the National Institutes of Health (NIH) is to solicit applications that support research on the neuroimmune mechanisms involved in the pathogenesis and pathophysiology of Chronic Fatigue Syndrome (CFS) and spectrum disorders in diverse groups and across the life span. Applications are encouraged from individuals who are part of multidisciplinary teams of scientists studying different aspects of CFS and its spectrum disorders. Chronic Fatigue Syndrome may be linked to dysregulation of at least two physiologic systems important for the maintenance of homeostasis: the central nervous system (CNS) (including the autonomic sympathetic system and the hypothalamic-pituitary-adrenal axis [HPA]) and the immune system. Several mediators may contribute to dysregulation, including activated immune cells, hormones, neurotransmitters, and others. Stress affects the activities of many of these mediators. Physiologic functions altered by stress and the ability to respond to stress likely play a role in the clinical manifestations of CFS. A variety of internal and external stressors lead to altered signaling in the central nervous and the immune systems. Whereas these changes are likely to contribute to or trigger disease symptomology, they may obscure the original stressor initiating the event.

Research at a systems level is needed to develop an understanding of the potential interactions of neural and immune systems in the disease process and to determine how alterations in integrated physiological systems affect the progression and nature of CFS. The NIH is soliciting applications that 1) examine mediators influencing central control mechanisms and communication among interacting components of the nervous and immune systems 2) apply new tools to explore different aspects of the disease process, 3) elucidate the development of influences that may enhance disease susceptibility and contribute to mechanistic aspects of this disease and 4) identify predictive biomarkers for CFS and/or spectrum disorders. The NIH is interested in funding research that will improve the diagnosis, treatment and quality of life of all persons with this disease, using the focus developed at the NIH sponsored CFS science workshop held in June 2003 “ Neuroimmune Mechanisms and Chronic fatigue Syndrome: Will Understanding Central Mechanisms Enhance the Search for Causes, Consequences, and Treatment of CFS?” This workshop summary is found at http://www4.od.nih.gov/orwh/CFS-newhome.html.

Background

Chronic Fatigue Syndrome is a complex disease that has had different names in the last two centuries, including neurasthenia, post viral fatigue, chronic mononucleosis, and myalgic encephalomyelitis. It has been proposed that CFS is one of a family of disorders that include fibromyalgia (FM), irritable bowel syndrome (IBS), posttraumatic stress disorder (PTSD), temporomandibular disorder (TMD), chemical sensitivities and others. The range of symptoms in CFS suggests that there may be perturbations in the central nervous and immune systems and in multiple physiological pathways through which these systems communicate and mediate each other. One of the most likely physiological pathways involved is the stress response, which is associated with physiological and pathological consequences. It can be triggered by a sequential or simultaneous combination of stressors, including infection, enzyme, gene, and cytokine abnormalities, hormonal fluctuations, and toxicant exposures that affect brain function. The stress response includes at least two components: the neuroendocrine stress response and the adrenergic sympathetic nervous system response. The neuroendocrine system responds to psychophysiological stress by releasing hormones of the HPA axis : the hypothalamus produces corticotrophin releasing hormone (CRH), the pituitary gland produces adrenocorticotropic hormone (ACTH), and the adrenal glands produce glucocorticoid hormones (GH).

In response to a stressor, the HPA axis releases glucocorticoid hormones that not only effect changes in peripheral organs and the brain, but also directly influence the immune system. The elaboration of cortisol and epinephrine are central to the stress response, but the release of other mediators including serotonin, norepinepherine, endogenous opioids, prolactin, and cytokines through this and other neuroendocrine systems, e.g. hypothalamic-pituitary-gonadal (HPG), and hypothalamic-pituitary-thyroid (HPT), may be involved. The finely tuned and adaptive response of the HPA axis prepares the immune system for the level of engagement (regional or systemic) needed to defend against infection or tissue damage. When the regulatory feedback loop of the CNS on the immune system is altered, disease symptomotology may manifest. Overactivation of the stress response depresses the immune system, whereas hypoactivation may predispose to inflammation. Prolonged demand, including chronic stress, on the stress response causes hyperactivation with overproduction and release of immunosuppressive glucocorticoids, culminating in susceptibility to infection, prolonged wound healing, and decreased antibody production to vaccine. In contrast, too little activation can result in unopposed inflammation and may lead to autoimmune inflammatory disease.

It has been suggested that stress induced increases in cortisol, through inhibition of CRH, inhibits the autonomic responses to subsequent stress. When autonomic function is tested in patients with fatiguing disease, including CFS, they show altered responses to stressors, which in some circumstances can be reversed by cortisol treatment. When the cortisol treatment is stopped however, the patients complain of fatigue, sleep disturbances, malaise, muscle aches, gastrointestinal complaints, cognitive problems, dizziness on standing, fever, and nausea, all signs of steroid withdrawal. Altered autonomic nervous system response may account for other features common to fatiguing syndromes, especially orthostatic intolerance resulting from an inability to synthesize norepinepherine.

There appears to be a correlation between the stress response and antidepressant action, a notion which may have clinical relevance for the development of symptoms in CFS. Stressed and non-stressed animals respond differently to antidepressants. Tricyclic antidepressants and serotonin reuptake inhibitors act by blocking the reuptake of monoamines, norepinephrine and serotonin respectively, into the neuron and increasing their circulating levels. Noepinephrine and serotonin affect mood, pain perception, sleep, and appetite, and trigger the acute release of stress hormones. The mechanisms and clinical implications of antidepressant actions in patients with CFS need to be better understood.

Physiologic functions altered by stress and the body's ability to respond to stress likely play a role in many clinical manifestation of CFS, including perhaps, sleep disturbance which is an important element of the CFS diagnosis. Dysregulation of endogenous circadian rhythms with sleep/wake cycle causes disturbed sleep, fatigue, impaired cognitive function, gastrointestinal upset, and poorly timed hormone release, all of which occur in CFS. Our knowledge of sleep regulation has been enhanced by investigations of the molecular changes associated with infectious disease. Acute infections usually present with fever and malaise, including a feeling of overwhelming sleepiness and profound fatigue. Peripheral cytokines produced in response to infection or other inflammatory stimuli are responsible for triggering the need to sleep, as well as changes in sleep patterns. They also are actively involved in regulating physiological sleep. A subclass of pro-inflammatory cytokines act not only locally, but also systemically to trigger all the classic responses to inflammatory challenge and inform the brain that the body is being threatened by invading microorganisms. It appears that both the pro-inflammatory cytokines and the anti-inflammatory cytokines regulate pathologic and physiologic sleep. Other systems are likely involved in sleep disturbances. Many CFS patients with insomnia demonstrate abnormal HPA axis and sympathetic outflow. In patients with insomnia both norepinepherine and epinephrine levels are significantly higher than in controls. Stress precipitates and perpetuates insomnia, which suggests a link between CRH and insomnia.

A better understanding of the integration of the immune system response with activity of the HPA axis and sympathetic nervous system may elucidate the onset, progression, and nature of the multiple symptoms of CFS and associated syndromes. The far reaching effects of both neuroimmune and neuroendocrine interactions need further study to elucidate the mechanisms of the disease and the treatment outcomes. It is also important to identify biomarkers for prediction and diagnosis, and mediators that may predispose to the disorder. Research that addresses these aspects of the disorder will ultimately lead to improved treatments, for fatigue and pain relief in all patients suffering from chronic fatiguing illnesses.

The NIH especially encourages individuals who are part of multidisciplinary teams of scientists studying different aspects of chronic fatigue syndrome and its spectrum disorders to submit applications in response to this RFA. Of particular interest, but not limited to, are applications that:

Applicants are encouraged to review recommendations from a NIH sponsored CFS science workshop held in June 2003 “Neuroimmune Mechanisms and Chronic Fatigue Syndrome”. This may be found at http://www4.od.nih.gov/orwh/cfs_june03report.pdf.

Within these general guidelines, some NIH Institutes have particular interests.

NIAAA encourages applications on alcohol health effects that are co-morbid with chronic fatigue syndrome.

NIEHS is particularly interested in applications that address the mechanisms by which environmental factors interact and/or disrupt communication between the immune and nervous systems as well as those that identify the mechanism by which environmental factors can alter susceptibility in utero and their consequences in adulthood.

NINDS is particularly interested in applications that address research in the area of dysregulation of circadian rhythms and sleep disorders, mechanisms underlying chronic pain, and the identification of genetic markers associated with neurological dysfunction associated with CFS and other fatiguing disorders.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the individual research project grant (R01) and the exploratory/development research grant (R21) award mechanisms . 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

The participating IC(s) ORWH, OBSSR, NIAAA, NIAMS, NIEHS, NINDS intend to commit approximately $4.0 Million dollars in FY 2006 to fund 6-10 new and/or competing continuation grants in response to this RFA. As an applicant you are solely responsible for planning, directing and executing the proposed project.

An applicant may request a project period of up to 4 years for R01 application and 2 years for R21 applications and a budget for direct costs up to $500,000 per year for R01 applications and $275,000 total direct costs for two year period for R21. (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html). This request should be tailored to the needs of the project. Since the nature and the scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary.

The anticipated start date for these awards is September 30, 2006.

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

Required meeting of all RFA funded grantees to be held after the second year of funding on the NIH campus to discuss Neuroimmune mechanisms and Chronic Fatigue Syndrome. Applicants should include a letter in their application stating their willingness to attend. Applicants should plan for this expense when preparing their budget.

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 Grants Info, 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 Dun & Bradstreet ( 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.

If an R21 is submitted, all rules as specified in the following link must be followed, http://grants.nih.gov/grants/funding/r21.htm.

3. Submission Dates and Times
Applications must be received 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: August 19, 2005
Application Receipt Date(s): September 19, 2005
Peer Review Date: January 2006
Council Review Date: May, 2006
Earliest Anticipated Start Date: July, 2006

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Office of Research on Women's Health
Dr. Eleanor Hanna
Senior Advisor to the Director
Office for Research on Women's Health
National Institutes of Health
Shannon Building, Room 201
Bethesda, MD 20892
Phone: (301) 402-1770
Fax: (301) 492-1798
Email : HannaE@od.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications 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).

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the participating organizations and ORWH Incomplete and non-responsive 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 review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

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

Special instructions for submissions of R21 applications can be found at http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.

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.

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/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.

The following will be considered in making funding decisions:

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by CSR in accordance with the review criteria stated below.

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

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

Office of Research on Women's Health (ORWH)
Dr. Eleanor Hanna
Associate Director for Special Projects and Centers
Office for Research on Women's Health
National Institutes of Health Shannon Building, Room 201
Bethesda, MD 20892
Phone: (301) 402-1770
Email: HannaE@od.nih.gov

Office of Behavioral and Social Science Research (OBSSR)
Dr. Susan Solomon
Senior Advisor
National Institutes of Health Shannon Building, Room 256
Bethesda, MD 20892
Phone: (301) 496-0979
Email: Ssolomon@nih.gov

National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Dr. Denise Russo
National Institute on Alcohol Abuse and Alcoholism/NIH
Division of Metabolism and Health Effects
5635 Fishers Lane, Room 2037
Bethesda, MD 20892-9304
Phone: 301-402-9403, Fax: 301-594-0673
Email: drusso@mail.nih.gov

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Dr. Deborah N. Ader
National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH
6701 Democracy Blvd., Suite 800
Bethesda, MD 20892
Phone: (301) 594-5032
Email: aderd@mail.nih.gov

National Institute of Environmental Health Science (NIEHS)
Dr. Annette Kirshner
National Institute of Environmental Health Science/NIH
Box 12233, MD EC-23
Research Triangle Park, NC 27709
Phone: 919-541-0488
Email: kirsner@niehs.nih.gov

National Institute of Neurological Disorders and Stroke (NINDS)
Dr. Linda Porter
Systems and Cognitive Science
6001 Executive Blvd., Room 2113
Bethesda, MD 20892-9521
Phone: (301) 496-9964
Email: lp216a@nih.gov

2. Peer Review Contacts:

Center for Scientific Review (CSR)
Dr. J. Terrell Hoffeld
Center for Scientific Review
National Institutes of Health
Rockledge 2 Building, Room 4116
6701 Rockledge Drive, MSC-7816
Bethesda, MD 20892-7816 (postal)
Bethesda, MD 20892-1813 (courier)
Phone: 301-435-1781
Email: th88q@nih.gov

3. Financial or Grants Management Contacts:

Terri Kendrix
Office for Research on Women's Health
National Institutes of Health Shannon Building, Room 201
Bethesda, MD 20892
Phone: (301) 402-1770
Email: KENDRIXT@od.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.


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NIH Funding Opportunities and Notices


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