Research on Etiological and Pathophysiological Mechanisms Underlying a Set of Chronic, Comorbid Conditions Associated with Temporomandibular Joint and Muscle Disorders (TMJMDs) (R03 Clinical Trial Not Allowed)

Research on Etiological and Pathophysiological Mechanisms Underlying a Set of Chronic, Comorbid Conditions Associated with Temporomandibular Joint and Muscle Disorders (TMJMDs) (R03 Clinical Trial Not Allowed) is sponsored by National Institute of Dental and Craniofacial Research (NIDCR) / National Institutes of Health (NIH). Research on Etiological and Pathophysiological Mechanisms Underlying a Set of Chronic, Comorbid Conditions Associated with Temporomandibular Joint and Muscle Disorders (TMJMDs) (R03 Clinical Trial Not Allowed) is sponsored by National Institute of Dental and Craniofacial Researc…

Expired PA-06-188: Temporomandibular Joint and Muscle Disorders: Pathophysiological Mechanisms Linking Comorbid Conditions (R01) This notice has expired. Check the NIH Guide for active opportunities and notices. Part I Overview Information Department of Health and Human Services Participating Organizations Institutes of Health (NIH), ( http://www.

nih. gov ) Components of Participating Organizations National Institute of Dental and Craniofacial Research (NIDCR), ( http://www. nidcr.

nih. gov ) Institute on Deafness and other Communication Disorders (NIDCD), (http://www. nidcd.

nih. gov ) National Institute of Neurological Disorders and Stroke (NINDS), (http://www. ninds.

nih. gov) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), (http://www. niams.

nih. gov) Research on Women’s Health (ORWH), (http://orwh. od.

nih. gov/ ) Title: Temporomandibular Joint and Muscle Disorders: Pathophysiological Mechanisms Linking Comorbid Conditions (R01) Update: The following update relating to this announcement has been issued: December 13, 2006 - The R01 portion of this funding opportunity has been replaced by PA-07-150 , which now uses the electronic SF424 (R&R) application for February 5, 2007 submission dates and beyond.

August 31, 2006 - See Notice NOT-DE-06-003 outlining additional information. March 24, 2006 - This announcement has been reissued as R03 ( PA-06-267 ) and R21 ( PA-06-268 ) funding opportunity announcements for the submission date of June 1, 2006 and submission dates thereafter.

Looking ahead: As part of the Department of Health and Human Services' implementation of e-Government, during FY 2006 the NIH will gradually transition each research grant mechanism to electronic submission through Grants. gov and the use of the SF 424 Research and Related (R&R) forms.

Therefore, once the transition is made for a specific grant mechanism, investigators and institutions will be required to submit applications electronically using Grants. gov.. For more information and an initial timeline, see http://era.

nih. gov/ElectronicReceipt/ . NIH will announce each grant mechanism change in the NIH Guide to Grants and Contracts ( http://grants.

nih. gov/grants/guide/index. html ).

Specific funding opportunity announcements will also clearly indicate if Grants. gov submission and the use of the SF424 (R&R) is required. Investigators should consult the NIH Forms and Applications Web site ( http://grants.

nih. gov/grants/forms. htm ) for the most current information when preparing a grant Program Announcement (PA) Number: PA-06-188 Catalog of Federal Domestic Assistance Number(s) (NIDCR), 93.

173 (NIDCD), 93. 853 (NINDS), 93. 846 (NIAMS) Release Date: March 1, 2006 Standard dates apply, please see http://grants1.

nih. gov/grants/funding/submissionschedule. htm for details.

dates apply, please see http://grants1. nih. gov/grants/funding/submissionschedule.

htm#reviewandaward for details. dates apply, please see http://grants1. nih.

gov/grants/funding/submissionschedule. htm#reviewandaward for details. Anticipated Start Date(s): Standard dates apply, please see http://grants1.

nih. gov/grants/funding/submissionschedule. htm for details.

Additional Information To Be Available Date (Url Expiration Date for R01 Non-AIDS Applications : November 2, 2006 Expiration Date for R01 AIDS and AIDS-Related Applications : January 3, 2007 purpose of this program announcement is to stimulate research on discovering etiological and pathophysiological mechanisms underlying a set of chronic, comorbid conditions associated with temporomandibular joint and muscle disorders (TMJMDs).

TMJMDs are a complex collection of diseases involving one or more tissues of the TMJ and facial musculature. Primary symptoms include chronic pain in facial muscles and limited and painful movement of the jaw.

In addition, these and other symptoms of TMJMD can occur together with other chronic illnesses such as fibromyalgia, atypical face pain, trigeminal neuralgia, chronic fatigue syndrome, multiple chemical sensitivity, irritable bowel syndrome, complex regional pain syndrome, migraine headache, speech hearing, swallowing, balance, smell, and taste disorders, and certain cardiovascular diseases.

This program announcement seeks research applications that use state-of-the-art, multidisciplinary and interdisciplinary approaches to discover molecular, physiological, and behavioral mechanisms responsible for the overlapping symptoms manifested in the set of disorders that may co-exist applications may have as their research focus the chronic, comorbid conditions themselves or TMJMDs, provided that the aims and goals of the project are to discover biological mechanisms linking the comorbidities.

While the overarching goal of this announcement is to arrive at a better understanding of potential mechanisms underlying TMJMDs as related to the variety of comorbidities associated with them, it is expected that no single research project will be able to accomplish this. Applicants are, therefore, encouraged to focus their attention on a particular pathway and a specific disease that is comorbid with TMJMD.

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. The total amount awarded and the number of awards will depend upon the mechanism numbers, quality, duration, and costs of the applications Program Announcement will use the R01 mechanism.

organizations include: For-profit organizations; non-profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; units of State government; units of local government; eligible agencies of the Federal government; foreign Institutions; domestic Institutions; and faith-based or community-based organizations.

principal investigators include any individuals with the skills, knowledge, and resources necessary to carry out the proposed research. Individuals are 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.

may submit more than one application, provided they are scientifically IV. 1 for application materials. for the hearing impaired is available at: TTY 301-451-5936 II Full Text of Announcement I.

Funding Opportunity Description 1. Mechanism(s) of Support III. Eligibility Information 2.

Cost Sharing or Matching 3. Other - Special Eligibility Criteria IV. Application and Submission Information 1.

Address to Request Application 2. Content and Form of Application 3. Submission Dates and Times A.

Submission, Review and B. Sending an Application to C. Application Processing 4.

Intergovernmental Review 6. Other Submission Requirements V. Application Review Information 2.

Review and Selection Process A. Additional Review Criteria D. Sharing Research Resources 3.

Anticipated Announcement and Award VI. Award Administration Information 2. Administrative and National Policy 1.

Scientific/Research Contact(s) 2. Peer Review Contact(s) 3. Financial/ Grants Management Contact(s) VIII.

Other Information - Required Federal Citations - Full Text of Announcement Section I. Funding Opportunity Nature of the research opportunity - The purpose of this Program Announcement is to encourage research leading to the discovery of possible etiological and pathophysiological mechanisms underlying a set of chronic disorders that may overlap with temporomandibular joint and muscle disorder (TMJMD).

Investigators with expertise in TMJMD and those with specific expertise in research areas related to the overlapping, comorbid conditions are encouraged to work together in carrying out cutting-edge research projects designed to uncover biological mechanisms responsible for comorbidities TMJMDs are a complex set of diseases involving one or more tissues of the face and TMJ.

The primary symptoms of TMJMD may include chronic pain in facial muscles and limited and painful movement of the jaw.

In addition, these and other symptoms of TMJMD may occur together with other chronic disorders such as fibromyalgia; atypical facial pain; trigeminal neuralgia; chronic fatigue syndrome; multiple chemical sensitivity; irritable bowel syndrome; sleep disorders; complex regional pain syndrome; migraine headache; speech, hearing (including tinnitus) swallowing, balance, smell, and taste disorders; affective disorders; and certain cardiovascular diseases.

The possible overlap of these other conditions with TMJMD suggests several possibilities: TMJMD coexists with other chronic diseases; TMJMD is the somatization of one or more of these conditions; TMJMD results from effects of the other chronic disorders; and/or TMJMD contributes to these other This initiative seeks research applications that will use multidisciplinary and interdisciplinary approaches to sort out these possibilities by discovering molecular, physiological, and behavioral mechanisms responsible for the overlapping symptoms and disorders that may coexist with TMJMD.

These applications may have as their research focus the chronic, comorbid conditions themselves or TMJMDs, provided that the aims and goals of the project are to discover biological mechanisms linking the comorbidities.

While the overarching goal of this announcement is to arrive at a full understanding of the mechanisms underlying TMJMDs and the variety of comorbidities associated with them, it is expected that no single research project will be able to accomplish this. Applicants, therefore, are encouraged to focus their attention on a particular pathway and a specific disease that is Background TMJMD is a complex heterogeneous disease.

It likely represents a collection of disorders with varying etiologies, affecting the tissues of the masticatory muscles and the temporomandibular joint. Due to this complexity and our lack of a complete understanding of the underlying mechanisms of disease onset and progression, the treatment of some patients with TMJMD currently is less than satisfactory.

The etiology of complex disorders like TMJMD may involve the interaction of genetic and environmental influences. In addition, it may be appropriate to view TMJMD as a biopsychosocial disorder, not only when considering diagnosis and treatment, but also in the context of pathological mechanisms associated with the disease and other diseases that may coexist with TMJMDs as comorbidities.

Peripheral defects in muscle function, abnormal neurotransmission, central integration of sensory and motor inputs, and the societal and cognitive influences on these processes, may all interact and influence the disease process and expression of the associated comorbidities.

The major symptoms of TMJMD are chronic myofacial pain particularly in the muscles of mastication, restricted range of jaw motion, jaw locking, and abnormal popping and clicking noises in the TMJ, although this latter symptom is not, by itself, either predictive or diagnostic of TMJMD.

In addition, other symptoms are known to occur in this disorder such as pain in the joint itself and in the area surrounding and radiating from the joint including the ear, neck, shoulder, and back; vertigo/balance problems; hearing loss, tinnitus; taste and smell problems; chronic headache; blurred or double vision; sleep disturbances; and difficulty in swallowing and/or speech.

Besides these symptoms, certain psychiatric disturbances (psychopathologies) may be associated with TMJMD and may include depression, anxiety disorders, and substance abuse. While these other symptoms and conditions are clearly not diagnostic of TMJMD, they are associated with other chronic painful disorders and may have an important role in developing treatment approaches for TMJMD patients.

For example, similar psychiatric disorders have been associated with TMJMD, fibromyalgia (FM), chronic fatigue syndrome (CFS), and irritable bowel syndrome (IBS). Interestingly, the psychiatric disorders are most often associated with the myogenous form of TMJMD (i.e. TMJMD characterized by chronic muscle pain) and may reflect the effects of prolonged chronic pain on the emotional status of the individual.

TMJMD patients often present with symptoms of other chronic painful conditions, such as FM, CFS, IBS, multiple chemical sensitivities, and cardiovascular abnormalities to name a few. As an example, both TMJMD and FM patients suffer from similar symptoms: muscle pain or tenderness, sleep disturbances, debilitating headaches, and difficulty in concentrating. The degree of overlapping symptoms and comorbid conditions is not trivial.

Studies suggest that between 13 and 18% of TMJMD patients meet the diagnostic criteria for FM. Conversely, about 75% of FM patients meet the criteria for myofacial TMJMD. Patients with IBS have been diagnosed at similar rates with comorbid TMJD (16%), CFS (14%), and FM (28-65%).

While some of the apparent comorbidity may be due to diagnostic ambiguity, it is clear that patients with these disorders have similar and multiple symptoms that characterize the various It is important to understand the basis for the links between these comorbidities in order to develop more effective treatment and possible prevention strategies for TMJMD.

However, the etiological and pathological mechanisms linking TMJMD and these comorbid conditions are unclear. In general they may involve abnormal responses of common homeostatic mechanisms, i.e. processes that help the body to return to original set points after a disruptive stimulus.

Alternatively, or in addition, the mechanisms may relate to allostatic processes, i.e. the adaptation to new set points in the continued presence of a stimulus or an altered environment. In addition, failed or repeated allostatic processes, i.e. the allostatic load, may account for these comorbidities. Most of these regulatory systems control a systemic, physiological response and a central behavioral, response.

The concept of faulty adaptive processes is in agreement with a shift in thinking in recent years to a more central nervous system focus as the cause of TMJMD (excluding TMJMD associated with traumatic injury) rather than simply a peripheral one employing local homeostatic mechanisms.

An additional consideration is that there is an increased prevalence of these comorbid disorders in women, indicating that sex steroids and gender may play an important, but complex role in the common pathophysiology. For example, there is an increased prevalence of TMJMD and FM in women, yet TMJMD patients are usually in their childbearing years while FM is usually diagnosed later in life.

Regardless of the mechanisms responsible for the comorbidities associated with TMJMD, a more precise determination of the phenotypes of the diseases will be critical in order to clearly identify subsets of TMJMD patients and the specific comorbid conditions associated with TMJMD.

While several distinct pathological mechanisms may account for the comorbidities seen in association with TMJMD, many seem to ultimately involve abnormal functioning of feedback circuits (both positive and negative).

These may include disturbances in the following: the hypothalamic-pituitary-adrenal (HPA) axis, the classical stress-response system; immune and neuroimmune function; centrally regulated biological clocks; autonomic nervous system function; and specific neurotransmitter system regulation. These and other mechanisms may work alone or in concert to cause the collection of comorbid conditions associated with TMJMD.

The cooperation of researchers with a common interest in TMJMD and those with specific expertise in research areas related to the overlapping comorbid conditions and symptoms found in TMJMD is needed in order to arrive at definitive answers to the underlying mechanisms involved in TMJMD and the variety of comorbidities noted.

Information from the fields of neurology, psychiatry, cardiology, genomics, endocrinology, epidemiology, rheumatology, and communicative disorders, to name a few, will be required to develop and test hypotheses relating to the mechanisms that can account for the cluster of comorbidities.

Technical expertise in behavioral science, genomic and proteomic approaches, biomedical imaging, electrophysiology, and molecular biology will be necessary to carry out cutting-edge experiments designed to uncover biological mechanisms responsible for overlapping symptoms and comorbid conditions associated with TMJMD.

While the overarching goal of this announcement is to arrive at a clearer understanding of the mechanism underlying TMJMD and the variety of comorbidities associated with it, it is expected that no single research project will be able to accomplish this. Applicants are, therefore, encouraged to focus their attention on a particular pathway and a specific disease that is comorbid with TMJMD.

Scientific knowledge to be achieved - This Program Announcement will stimulate research that will increase our knowledge of the etiological and pathological mechanisms underlying comorbidity in somatic syndromes like TMJMD. It will be important to identify the regulatory systems and the altered functions of these systems that are important in the expression of comorbidity.

Knowledge of both physiological and behavioral responses that are central in eliciting comorbidity will be gained; the molecules and cellular pathways underlying these responses will be identified as well.

Objectives of this research program - The objectives of this Program Announcement are to stimulate research that will: 1) identify molecules, cellular pathways, physiologies, and behaviors that are responsible for comorbid conditions that may be associated with TMJMD; 2) determine the pathogenic mechanisms by which these factors lead to the comorbidities; 3) determine molecules and pathways that may serve as novel therapeutic targets aimed at treating these comorbid conditions and/or preventing them; 4) identify biomarkers or diagnostics that will differentiate refractory TMJMD and comorbid conditions from those disorders which spontaneously remit or are successfully treated by conventional means.

Identify types of research and experimental approaches that This Program Announcement seeks applications that will use basic, behavioral, epidemiological, and clinical research approaches in order to define causative factors and characterize pathogenic mechanisms that may be shared between comorbid conditions and TMJMD.

This Announcement seeks a broad range of experimental approaches to this problem and may include clinical, molecular, cellular, and animal studies. The use of global approaches such as a systems biology approach and the utilization of genomic and proteomic techniques also are encouraged.

Investigators with expertise in the fields of neurobiology, immunology, neurochemistry, endocrinology, rheumatology, cognitive and behavioral neuroscience, sensory and motor systems, neurology, and bioinformatics will be needed to discover biological mechanisms underlying Examples of research topics Examples of research topics may include, but are not limited to the following, as they relate to TMJMD and molecular mechanisms in the central nervous system that modulate peripheral nociceptive neurotransmission that identify genes and gene polymorphisms that are causative or produce risk factors for comorbid conditions and TMJMD inflammatory pain and proinflammatory cytokines on hypersensitivity of central hypersensitive nociceptive pathways on the HPA axis molecules and pathways that regulate or disrupt circadian rhythms and other to identify brain regions and nerve tracts active in patients with TMJMD and determine the influence of the activity of nociception pathways on other sensory and motor systems including taste, smell, hearing (including tinnitus) balance, speech, swallowing, and vision models to examine the effects of chronic pain on affective behaviors influence of sex hormones on circadian rhythms, HPA axis, and autonomic nervous trigeminal nerve activity on the autonomic nervous system and the HPA axis on the effects of neural plasticity in pain pathways that effect other sensory approaches that help to discover behavioral changes influencing and influenced by TMJD and comorbid conditions VIII, Other Information - Required Federal Citations , for policies related 1.

Mechanism(s) of Support opportunity will use the R01 award mechanism. will be solely responsible for planning, directing, and executing the proposed 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. scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary.

Although the financial plans of the Institutes and Centers (ICs) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004 . III. Eligibility Information 1.

A. Eligible Institutions application(s) if your organization has any of the following characteristics: or private institutions, such as universities, colleges, hospitals, and agencies of the Federal government or community-based organizations 1. B.

Eligible Individuals 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 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 IV. Application and Submission Information 1.

Address to Request Application Information 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) 710-0267, Email: [email protected] .

the hearing impaired: TTY 301-451-5936. 2. Content and Form of Application Submission 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 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 Several special provisions apply to applications submitted by foreign organizations: back of customs and import fees is not allowed.

every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8. 5" x 11." for up to 8% administrative costs (excluding equipment) can now be requested ( http://grants.

nih. gov/grants/guide/notice-files/NOT-OD-01-028. html ) must comply with federal/NIH policies on human subjects, animals, and must comply with federal/NIH biosafety and biosecurity regulations.

See Section VI. 2 . Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

research should provide a unique research opportunity not available in the U.S. 3. Submission Dates and Times See Section IV. 3.

A for details. Submission, Review and Anticipated Start Dates Date(s): http://grants1. nih.

gov/grants/funding/submissionschedule. htm Peer Review Date(s): http://grants1. nih.

gov/grants/funding/submissionschedule. htm#reviewandaward Review Date(s): http://grants1. nih.

gov/grants/funding/submissionschedule. htm#reviewandaward Earliest Anticipated Start Date(s): http://grants1. nih.

gov/grants/funding/submissionschedule. htm not required for the funding opportunity. prepared using the research grant application forms found in the PHS 398 instructions for preparing a research grant application.

Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 (U.S. Postal Service Express Bethesda, MD 20817 (for express/courier service; applications are no longer permitted (see http://grants. nih. gov/grants/guide/notice-files/NOT-OD-03-040.

html ). Applications must be submitted on or before the application receipt/submission dates described above ( Section IV. 3.

A. ) and at http://grants. nih.

gov/grants/dates. htm . applications will be evaluated for completeness by CSR.

Incomplete applications any application in response to this funding opportunity that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed.

This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. 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 subject to intergovernmental 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 . 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 Instructions for Modular Grant applications. 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 .

Instructions for Applications Requesting $500,000 (direct costs) or More per $500,000 or more in direct costs for any year must carry out the following program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; from the IC staff that the IC will accept your application for consideration 3) Include a cover letter with the application that identifies the staff member and IC who agreed to accept assignment of the 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 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. more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application.

The funding organization will be responsible for monitoring the data sharing policy ( http://grants. nih. gov/grants/policy/data_sharing ).

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

Sharing Research Resources 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 ). V. Application Review Information criteria described below will be considered in the review process.

2. Review and Selection Process 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. merit review, all applications will: selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score. level of review by an appropriate national advisory council or board.

considered in making funding decisions: of the proposed project as determined by peer review 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?

criteria, the following items will continue to be considered in the determination of scientific merit and the priority score: of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 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,