Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Institute of Neurological Disorders and Stroke (NINDS) National Institute of Mental Health (NIMH)
Funding Opportunity Title	Centers for Collaborative Research in Fragile X (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	Reissue of RFA-HD-07-013
Related Notices	November 16, 2012 - See Notice NOT-HD-12-034. Clarification of Budget Instructions. October 5, 2012 - See Notice NOT-HD-12-031. Informational/Technical Assistance Pre-application Meeting for this RFA.
Funding Opportunity Announcement (FOA) Number	RFA-HD-13-004
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.865; 93.242; 93.853
Funding Opportunity Purpose	This funding opportunity announcement (FOA), through an open competition, solicits applications for Centers for Collaborative Research in Fragile X. Successful Centers will be composed of transdisciplinary teams of investigators working together to address specific scientific questions within targeted areas of research. The targeted areas of research are intended to address research gaps, drive discovery and further develop research relevant to Fragile X syndrome and (Fragile X Gene) (FMR1) Related Conditions. Targeted areas of research include: A) Advancing the understanding of the pathophysiology of FMR1 Related Conditions B) Facilitating the Development of Treatments for FMR1 Related Conditions C) Advancing the knowledge of clinical phenotypes for FMR1 Related Conditions. The Centers of Collaborative Research in Fragile X will be established using a linked U01 mechanism. Each Center will consist of 1) an administrative core and 2) three distinct but highly integrated research projects. Other shared resource cores may be proposed if appropriate to the project and goals of the proposed Center and if they fit within the budgetary constraints of the Center as a whole.

Posted Date	October 2, 2012
Open Date (Earliest Submission Date)	December 30, 2012
Letter of Intent Due Date	December 30, 2012
Application Due Date(s)	January 30, 2013, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	June/July 2013
Advisory Council Review	August 2013
Earliest Start Date(s)	September 2013
Expiration Date	January 31, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The Fragile X Syndrome Research Centers were originally developed in response to the Children's Health Act of 2000 (H. R. 4365) Section 452E which called for the funding of three Centers. Over the past ten years, the funded Centers have produced numerous findings that have propelled the field of Fragile X research forward at a rapid pace.

This FOA, through an open competition, solicits applications for Centers for Collaborative Research in Fragile X. Successful Centers will be composed of transdisciplinary teams of investigators working together to address specific scientific questions within targeted areas of research. The targeted scientific questions are intended to address research gaps, drive discovery and further develop research relevant to Fragile X syndrome and Fragile X Gene (FMR1) Related Conditions.

Collectively, Fragile X syndrome (FXS), Fragile X Associated Tremor/Ataxia syndrome (FXTAS), and Fragile X Associated Primary Ovarian Insufficiency (FXPOI), along with other FMR1 Related Conditions, represent a major health concern and have far-reaching implications for individuals, families, and their future generations.

While FXS, FXTAS and FXPOI have very different clinical symptoms, they all result from variations in a region of the FMR1 gene that contains multiple repeats of three nucleotides, cytosine-guanine-guanine (CGG). The specific repeated pattern and differences in the number of CGG repeats in the gene determine the most common forms of the gene: premutation and full mutation.

Individuals with fewer than ~55 repeats are considered to have a normal FMR1 gene. Individuals with more than 200 repeats have a full mutation and FXS. Full mutations are generally associated with intellectual and development disabilities (IDD) apparent in early childhood. Repeats in the range of ~55 to 200 are called premutations and are associated primarily with adult-onset disorders: FXTAS and FXPOI. Collectively, "FMR1 Related Conditions" refers to any of the clinical conditions due to an abnormal FMR1 allele (premutation or full mutation) and includes FXS, FXTAS, FXPOI, and others.

Fragile X Syndrome (FXS)

FXS is the most common inherited cause of IDD and has been estimated to occur in approximately 1 in 2,500 males and females across all racial and ethnic groups. IDD in FXS ranges from mild to severe, and females are more mildly affected, on average, than males because of the potential for favorable X inactivation in females. Emotional and behavioral problems, including attention problems, hyperactivity, anxiety, mood instability, tantrums, aggression, and social deficits, are common. As many as 30 to 50 percent of individuals with FXS meet the diagnostic criteria for autism or autism spectrum disorders (ASDs). FXS is considered a portal for understanding a variety of neurobehavioral disorders, including autism, attention-deficit hyperactivity disorder (ADHD), and anxiety disorders.

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)

The core features of FXTAS are intention tremor and/or ataxia, with gradual cognitive decline beginning with memory and executive function deficits. Psychiatric problems including anxiety, dysinhibition, depression, and apathy are also common. Associated clinical features include peripheral neuropathy, dysautonomia, and particularly in women with FXTAS, hypothyroidism and muscle pain/fibromyalgia. Symptoms of FXTAS typically appear after age 50, although the age of onset correlates with the CGG expansion within the premutation range the higher the number of repeats, the earlier the onset of tremor or ataxia. The penetrance of FXTAS is incomplete, meaning that not all carriers develop symptoms, and men are more commonly affected than women. Preliminary data on life expectancy from age of onset are variable, with a range from five to 25 years.

Fragile X-associated Primary Ovarian Insufficiency (FXPOI)

Women with the fragile X premutation are at risk for primary ovarian insufficiency, which is the onset of menopausal symptoms before the age of 40 years, and reflects a continuum of ovarian function. Fragile X premutation carriers, as a group, experience menopause approximately five years earlier than normal women, and women with the premutation who still have regular menstrual cycles show indications of early ovarian aging. Women with FXPOI not only experience loss of normal fertility but are also at increased risk for osteoporosis and cardiac disease and have higher rates of mortality. Thus, women who have a fragile X premutation face the increased health risks related to FXPOI and FXTAS as well as the risk that their children will inherit the unstable repeat as either the pre- or full mutation.

Other FMR1 Related Conditions

In addition to carrying a risk for later developing FXTAS and if female, FXPOI, premutation carriers have been reported in the literature to show symptoms as children that may include ADHD, anxiety, shyness, social deficits, and, on occasion, autism spectrum disorders. Boys appear to be affected more often than girls. However, further research is needed to fully understand these findings.

Development of Research Objectives

In the spring of 2008, the NIH, in response to a request from the U.S. Department of Health and Human Services and the Senate Committee on Appropriations, convened working groups charged with developing the NIH Research Plan on Fragile X and Associated Disorders. The plan consisted of comprehensive recommendations for specific, high-priority research objectives for FXS and the associated disorders of FXTAS and FXPOI. The goals were designed to be used by the NIH and FXS, FXTAS, and FXPOI research communities and to be shared with other federal agencies to facilitate coordinated research activities that could lead to timely detection, diagnosis, treatment, and prevention of the targeted disorders.

In spring 2012, the NIH published a Request for Information (RFI) entitled, Research Priorities in Fragile X syndrome, Fragile X Tremor Ataxia syndrome, Premature Ovarian Failure and Other Relevant Conditions Associated with FMR1 Gene Function (NOT-HD-08-003) requesting comments from the scientific community, health professionals, patient advocates, and industry regarding future research priorities for these disorders. On May 7-8, 2012, the NICHD convened a meeting, Revisiting the NIH Research Plan on Fragile X and Associated Disorders, with the intent of reevaluating the existing goals of the Research Plan and providing input to determine whether progress was being made in meeting the goals or if it was necessary to modify the goals or add new ones. Participants in the meeting included scientific experts from the research and clinical communities, along with representatives from advocacy groups for affected individuals and family members, other pertinent federal agencies and invested NIH Institutes and Centers (ICs).

The specific areas of research interest for this FOA are derived from the original NIH Research Plan on Fragile X and Associated Disorders, responses to the RFI, discussions during the meeting reevaluating the research plan, and the priorities and missions of ICs participating in the FOA.

For the purposes of this FOA three areas of targeted research have been identified as being of specific interest:

• Advancing the understanding of the pathophysiology of FMR1 Related Conditions
• Facilitating the development of treatments for FMR1 Related Conditions
• Advancing the knowledge of clinical phenotypes for FMR1 Related Conditions

Applicants for each Center of Collaborative Research in Fragile X must identify one of the broad areas of research.

Center projects must be submitted as linked U01 applications. Each program will consist of 1) an administrative core, and 2) three scientific projects. Other shared resources cores will be accepted if appropriate.

Each of the scientific projects should:

1) Be relevant to the overall research focus of the center.

2) Address one or more of the research gaps or needs listed below.

3) Be fully integrated with other scientific projects within the Center.

3) Must have goals and aims that will be completed and will significantly benefit the field within the five-year period of the award.

A. Advance the understanding of the pathophysiology of FMR1 Related Conditions

Targeted topics of research may address one or more of the following:

Fragile X Syndrome

• Determine the molecular function(s) of FMRP and the macromolecules (FXR1, FXR2, mRNAs, non-coding RNAs, proteins) with which it interacts in cellular processes and compartments.
• Understand the regulation of Fmr1 expression and FMRP levels (transcriptional, translational, turnover) and the function of posttranslational regulation of FMRP in cellular processes.
• Examine if and how dysregulation of specific mRNA targets of FMRP leads to functional, structural or behavioral phenotypes.
• Determine the impact of FMRP deficiency on synapses, plasticity, neuronal connectivity, circuitry and neural systems in humans and animal models relevant to behavioral phenotypes.
• Delineate the temporal and spatial role of FMRP in FXS-relevant phenotypes.

Fragile X Associated Tremor/Ataxia Syndrome

• Define the relative contributions of specific molecular mechanisms (e.g., expanded CGG-repeat FMR1 mRNA and lower level of FMRP) to FXTAS pathogenesis.
• Identify the cellular and molecular abnormalities caused by the premutation expansions in both neuronal and non-neuronal cell populations across the lifespan.
• Define the mechanisms leading to overexpression of sense and antisense transcripts at the Fmr1 locus.
• Identify the molecular basis for incomplete penetrance of FXTAS, including gender-specific differences, and the extent to which penetrance reflects second-gene effects and/or environmental factors.
• Determine the mechanism of formation and pathogenic significance of the intranuclear inclusions of FXTAS.
• Define how alterations in cellular homeostasis (e.g. protein quality control, mitochondrial dysfunction, RNA processing, miRNA expression, etc) contribute to FXTAS pathogenesis.

Fragile X Associated Primary Ovarian Insufficiency

• Develop model systems in which expanded FMR1 CGG repeats induce the reproductive phenotype observed in humans in order to identify a mechanism and determine the time course of reproductive function.
• Elucidate the association between FMR1 repeat structure and biomarkers associated with the reproductive phenotype in women to predict development of FXPOI and identify its mechanism.
• Determine the specific molecular mechanism, including environmental triggers, epigenetic changes, etc. that cause the CGG repeat to lead to the impairment of a woman’s reproductive system.
• Identify targets and develop drug screens for FXPOI.

Genetic Basis for FMR1 Disruptions

• Determine the molecular mechanisms that lead to CGG repeat mutations and the consequences that alter FMR1 gene expression, including modifications in regulatory and promoter regions as well as epigenetic modifications that lead to transcriptional silencing or abnormal transcription.
• Develop models to study mechanisms of CGG repeat expansions, Fmr1 gene silencing in order to test therapeutics for unsilencing or selective reactivation.
• Identify the cellular and molecular abnormalities caused by the premutation expansions in both neuronal and non-neuronal cell populations across the lifespan.
• Identify the molecular basis for incomplete penetrance of FMR1 Related Conditions, including gender-specific differences, and the extent to which penetrance reflects second-gene effects and/or environmental factors.
• Identify how the repeat expansion could modulate other diseases.

B. Facilitate the Development of Treatments for FMR1 Associated Disorders

Targeted topics of research may address one or more of the following:

Fragile X Syndrome

• Develop assays of Fmr1/FMR1 expression or FMRP function that are amenable to high throughput screening of potential therapeutics.
• Develop, evaluate and adapt educational and behavioral interventions including early intervention for individuals with FXS and evaluate use of these in combination with pharmacological interventions.
• Identify the best timing of treatments and interventions across the lifespan for individuals with FXS.

Fragile X Associated Tremor/Ataxia

• Evaluate existing supportive devices and physical therapies to determine if these improve outcome (e.g., increase time to becoming wheelchair-bound) or lengthen survival of persons with FXTAS.
• Utilize screening techniques that test the effect of large numbers of agents in cell culture and in animal models in modulating the molecular and cellular consequences of the FXTAS mutation (e.g., reducing the toxic mechanisms).
• Develop cell-based assays that target aspects of pathogenesis and pathophysiology in FXTAS.
• Validate preclinical models of FXTAS for improving efficiency in human trials.

FMR1 Related Conditions

• Evaluate currently available pharmaceutical treatments targeted at specific symptoms in FMR1 Related Conditions.
• Identify potential biomarkers of FMR1 related conditions, incorporating diverse technologies, approaches, and models as markers of phenotype severity and treatment outcomes.
• Evaluate new drugs currently in development that are targeted to FMR1 Related Conditions symptoms in trials in animal models and human clinical trials.
• Develop a standard battery of functional, objective measures to describe behavioral and psychosocial effects in FMR1 premutation carriers across the lifespan and serve as indicators of treatment need and efficacy.
• Establish standardized endpoints for preclinical trials in animal models that enable testing of drugs and other therapeutic approaches.
• Validate a reliable and sensitive FMRP assay that can be used as a biomarker across laboratories for comparative studies.
• Leverage knowledge across neurodevelopmental disorders about shared biological pathways to design treatment studies.

C. Advance the Knowledge of Clinical Phenotypes for FMR1 Related Conditions

Targeted topics of research may address one or more of the following:

Fragile X Syndrome

• Natural history studies that characterize the dynamic nature of the FXS phenotype across the lifespan and that identify moderators and mediators of the phenotype.

Fragile X Associated Tremor/Ataxia Syndrome

• Define the relationship between the FXTAS clinical phenotype, FMR1 molecular genetic abnormalities, imaging, tissue pathology and measures of cellular dysfunction; identify factors (e.g., molecular, clinical, environmental) associated with various FXTAS clinical signs.
• Define the prevalence of the FMR1 allele lengths, including gray zone, in the general population ascertained in an unbiased fashion. Categorize these data for age across numerous age cohorts.
• Determine the prevalence of elongated FMR1 alleles, including gray zone, in adults with memory impairment or dementia (e.g., Lewy body dementia, Alzheimer disease), Parkinsonism/tremor, ataxia, dysautonomia, and/or peripheral neuropathy.
• Identify potential familial predisposition to FXTAS, its association with FXPOI and FXS, and identify molecular factors involved in family clustering.
• Determine best practices for ascertainment of premutation carriers and FXTAS cases.

Fragile X Associated Primary Ovarian Insufficiency

• Elucidate associations between CGG repeat structure across the entire range of allele sizes and various indications of ovarian function in women, using cross-sectional and longitudinal study designs.
• Identify biomarkers that predict reproductive health in women with high risk FMR1 alleles and establish a prospective study to determine their efficacy.
• Characterize the menopausal transition and postmenopausal health of women with FXPOI and determine whether these characteristics differ from those in other women with idiopathic premature ovarian insufficiency or women with natural menopause.
• Determine whether high risk FMR1 alleles are associated with fertility treatment outcomes.
• Determine whether high risk FMR1 alleles are associated with adverse pregnancy outcomes.
• Assess whether genetic and environmental factors known to affect reproductive function contribute to or modify age of onset and severity of FXPOI using both human and animal model systems.

FMR1 Related Conditions

• Define the range of behavioral, psychiatric, neurological and other medical (e.g., cardiac, endocrine, etc.) dysfunction associated with premutation carriers through study of affected and at-risk persons.
• Prospectively identify the natural history of the FMR1 premutation carrier and the progression of FMR1 Related Conditions, including factors associated with rapid and slow progression of disease.
• Define the relationship between the FMR1-associated clinical phenotypes, FMR1 molecular genetic abnormalities, imaging, tissue pathology and measures of cellular dysfunction; identify factors (e.g., molecular, clinical, environmental) associated with various FXTAS and/or FXPOI clinical signs.
• Prospectively identify the natural history of the FMR1 premutation carrier and development and progression of an FMR1 Related Condition, including factors associated with rapid and slow progression of disease.
• Identify novel genetic and epigenetic factors, including genomic approaches that contribute to or modify age of onset and severity of FMR1 related conditions using both human and model systems.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The NICHD and partner components of NIH intend to commit the following estimated total amounts in FY 2013: NICHD, $4 million to support up to 3 Centers NINDS, $275,000 to support one project NIMH, $2 million
Award Budget	Individual linked U01 application budgets should reflect the actual needs of the proposed projects. Budgets for each Center (made up of linked U01 awards) may not exceed $1.3 million total costs per year.
Award Project Period	The scope of the proposed project should determine the project period but is limited to a maximum of 5 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• System for Award Management (SAM) must maintain an active entity registration (formerly CCR registration), to be renewed at least annually. Use the SAM.gov Manage Entity function to manage your entity registrations. See the Grants Registration User Guide at SAM.gov for additional information.
• Grants.gov
• eRA Commons

All Program Directors/Principal Investigators (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director/Principal Investigator (PD/PI) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

Because the Collaborative Centers for Research in Fragile X program is intended to support projects conducted by multidisciplinary teams, multi-site applications are strongly encouraged.

Center projects will be submitted as linked U01 applications. This arrangement provides each PD/PI a unique cooperative agreement award, but the component U01 is clearly an integrated part of the overall multidisciplinary Center program. Each Center for Collaborative Research in Fragile X must designate a single PD/PI as the Center Director (CD). This individual will be responsible for coordination of the multiple facets of the individual center as well as communication across the Centers for Collaborative Research in Fragile X.

Centers are encouraged to include investigators whose primary field of expertise is outside of Fragile X but whose inclusion provides a significant, relevant contribution to the project. This is intended to enrich the perspectives and methodologies brought to bear in addressing the targeted areas of research.

In addition, multidisciplinary teams are strongly encouraged to consider having early-stage or new investigators participate in each of the scientific components of the project.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research
• Name, address, and telephone number of the PD(s)/PI(s)
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

The letter of intent should be sent to:

Tiina K. Urv, PhD
Intellectual and Developmental Disabilities Branch
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
6100 Executive Blvd.
Bethesda, MD 20892-7510
Rm 4B09D, MSC 7510
Phone: (301) 402-7015
Email: [email protected]

The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with Research Strategy page limits as follows:

Administrative Core - 6 pages

Research Projects - 12 pages each

Shared Resource Core(s) - 6 pages each

Each Center application should include the following components:

• 1 Administrative Core
• 3 Research Projects
• Shared Resources Cores (if appropriate)

Each component of the Center for Collaborative Research in Fragile X should be submitted as an individual U01.

The title of each Center should be unique (do not repeat the title of this FOA).

The title of the Center should be the same for all components associated with the linked application and should include the suffix "(1 of n)", with "n" equaling the total number of linked applications or "(2 of n)" or "(3 of n)" to allow for the identification of the linked applications for each center.

• The Administrative Core should be (1 of n)
• Research Projects should follow the Administrative Core: (2 of n), (3 of n), (4 of n)
• Shared Resources Cores (optional) should follow the Research Projects (5 of n), etc.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Administrative Core

The PD/PI of the Administrative Core will serve as the overall Center Director. The Administrative Core application should address:

• Which targeted area of research the Center has chosen to address?
• The relevance of the research to Fragile X and FMR1 Related Conditions and how it will benefit the field.
• Specific Aims for the overall Center.
• A detailed description of and interdependent associations between the Research Projects of the Center (and any other Cores), including a description of how each Research Project will be integrated into the overall Center.
• A table or schematic that briefly summarizes the collaborative activities across sites.
• A description of the management structure, leadership roles, and mechanisms of communication between the Center's projects.
• Information on an agreed-upon charter for the Center and rules for authorship and ownership of data.
• How assistance in preparation of collaborative presentations, manuscripts and progress reports will be provided.
• Establishment of a Steering Committee for the Center comprised of all participating U01 PD(s)/PI(s), the Center Director, and the associated NIH Program Scientists.
• Scheduling and provision of logistical support for site meetings and teleconferences:
• A Steering Committee conference call should occur at a minimum of once a month and should be a component of the Center operations.
• The administrative core should plan to organize a virtual/or in-person meeting of the key center research personnel at least one time per year.
• Steering Committee members will participate in an all-Centers meeting for the Collaborative Centers for Research in Fragile X once a year in Bethesda, MD and should budget for this travel.

Research Projects

Applications for Research Projects should address:

• Which research questions(s) the individual Research Project has chosen to address.
• The relevance of the specific project to the Center.
• Relevance of the research to Fragile X and/or FMR1 Related Conditions and how the results of the research will benefit the field.
• Interactions/synergies with other Research Projects
• Interactions with Cores and utilization of Core services/resources

To assess the predictive value of preclinical research for therapeutic development, sufficient information must be presented about the proposed study design, execution, and interpretation of the supporting data or results in the grant application.

Critical elements of a well-designed study include:

• adequate scientific rigor
• control of bias
• reproducibility
• dose-response
• confirmation of mechanism
• transparency of reporting

Applicants are strongly encouraged to leverage existing infrastructure resources.

Shared Resource Core(s)

Applications for Shared Resource Core(s) should address:

• How this core will be used by each of the scientific projects

Shared Resource Cores must not duplicate analogous resources already established in the applicant institutions, although supplemental funding to such existing resources may be requested. Each Shared Resource Core must have a single designated PD/PI who will serve as the Core Director.

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modifications:

• Projects relevant to autism research are encouraged to consider sharing data within the following mechanism: The NIH National Database for Autism Research (NDAR) houses research data of all types (genetic, imaging, clinical assessment, etc.) from human subjects involved in ASD studies, and is currently on track to receive data from tens of thousands of such subjects. NDAR’s first data release occurred in November 2010, making mostly clinical assessment data from over 10,000 research subjects available to qualified investigators. It is expected that in the next several years, ASD data from more than 90% of new investigations will be available in or through NDAR. For more information on NDAR, please visit http://ndar.nih.gov/ndarpublicweb/.

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by NICHD, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed. In order to be considered responsive to the FOA, each Center application must include at minimum:

• An Administrative Core submitted as a linked U01
• Three highly integrated Research projects submitted as linked U01s

The NIH will hold a pre-application informational conference call on November 5, 2012, from 1:30 pm - 3:00 pm EST, which all interested prospective applicants are invited. Program and review staff will make presentations to explain the goals and objectives of the FOA and answer questions from call participants.

To obtain the call-in information, please contact Dr. Tiina Urv ([email protected] or 301-402-7015) at least 24 hours prior to the call.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Is there integration of the linked components, including a feasible management plan?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Administrative Core

• Is the application equally strong across all projects?
• Do the Cores/Projects collectively address one of the proposed targeted areas of research?
• Does the Administrative Core provide strong coordination/integration for the Center?
• Is the leadership/management plan effective?

Research Projects

• Is the individual scientific project relevant to the targeted area of research of the Center as a whole?
• Do the scientific projects that are preclinical in nature include adequate scientific rigor, control of bias, reproducibility, dose response, confirmation of mechanism, and transparency of reporting?

Shared Resource Core(s)

• Is the Core relevant to the project Center as a whole?
• Will there be sufficient utilization of the Core by the Research Projects?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.

Not Applicable

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NICHD, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact/priority score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• The overall function of the Center as described under "Specific Research Objectives". This includes the development of the standard operating procedures, and consistent emphasis on collaborative interactions between all Center investigators, advisory and steering committees, and NIH representatives. Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• An NIH Project Scientist will be responsible for: (1) overseeing the activities of the Center, along with the other entities delineated above, to ensure that studies are properly conducted and completed in a timely fashion; (2) providing advice and guidance to ensure that the Center runs in accordance with NIH policies and procedures, and is consistent with the mission of the NIH to improve public health; and (3) serving as a point of contact for investigators with the NIH (4) disseminating information from the Institute and communicating with Institute leadership to ensure that the Center operates smoothly.
• An NIH Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• The NIH will appoint an Advisory Board for the entire Centers for Collaborative Research in Fragile X Program. It is expected that this Board will include representatives from academia, industry, other government agencies, and non-profit organizations. The role of this Advisory Board will include discussion of direction of projects, including vision for integration of studies and how they can best serve the overall goals of the project and stakeholders.

Areas of Joint Responsibility include:

• The NICHD Project Scientist and staff will work closely with the Advisory Board, the Steering Committees, and the PD(s)/PI(s) of all Projects and Cores in order to ensure proper conduct of the Center.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]

Tiina K. Urv, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone 301-402-7015
Email: [email protected]

Lisa Gilotty, PhD
National Institute of Mental Health (NIMH)
Telephone: 301-443-3825
Email: [email protected]

Robert Riddle
National Institute of neurological Disorders and Stroke (NINDS)
Telephone: 301.496.5745
Email: [email protected]

Laura Mamounas, Ph.D.
National Institute of neurological Disorders and Stroke (NINDS)
Telephone: 301.496.5745
Email: [email protected]

Sherry Dupere, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-3415
Email: [email protected]

Bryan Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: [email protected]

Rebecca Claycamp, MS, CRA
National Institute of Mental Health (NIMH)
Telephone: 301-443-2811
Email: [email protected]

Tijuanna DeCoster, MPA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: (301) 496-9231
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.