Notice Number: NOT-MH-10-024
Update: The following update relating to this announcement has been issued:
Release Date: July 16, 2010
Application Due Date: September 25, 2010 (Changed to September 24, 2010 per NOT-MH-10-032)
Earliest Anticipated Start Date: December 1, 2010
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov)
The purpose of this notice is to encourage applications for competitive revisions to research projects currently funded by the NIMH U24 cooperative agreement mechanism, appropriate to establish a repository/resource for postnatal-to-adult human control and patient-derived cells and their reprogrammed derivatives; this repository will support stem cell research relevant to mental disorders. It is expected that the repository will be staffed by a team of investigators with expertise in patient sample collection, cellular and molecular biology, with the ability to effectively interface with experts in computer and information sciences, statistical genetics and psychiatric genetics. This effort may involve activities at multiple institutions that are strategically and functionally coordinated such that the repository will function as a single, national resource. A critical feature of the repository is that it will be integrated into the NIMH Center for Collaborative Genetic Studies on Mental Disorders (http://zork.wustl.edu/nimh/home/NIMH_Gen_Initiative.html), which currently provides bioinformatics infrastructure to support current and future discoveries in the genetics of mental disorders.
The study of cognitive, mood and social disorders currently suffers from a gap in understanding fundamental molecular and cellular defects and the role of altered developmental processes in these disorders. The ability to generate models that could address this gap is often hindered by the absence of an obvious human lesion or single gene mutation that can be replicated in animals. Some current pre-clinical models of schizophrenia, for example, relate to the improvement seen in patients after treatment with drugs acting on dopamine systems or the generation of psychosis-like symptoms in response to glutamate receptor antagonists. This led to the idea that dopaminergic and glutamatergic neuronal pathways are dysfunctional in schizophrenia. However, other lines of evidence implicate genes involved in the migration, differentiation, and maturation of multiple cell types in the developing nervous system, including GABAergic neurons. This suggests that studies targeting a single gene or neurotransmitter pathway provide only a limited window into the developmental history and pathophysiology of schizophrenia or other mental disorders.
The recent development of human induced pluripotent stem cells (iPSCs) may offer a unique opportunity to address this experimental dilemma. iPSCs are similar to embryonic stem cells (ESCs) in that they exhibit pluripotency, the ability to generate all body cell types – including neurons (Dimos et al., 2008, Science 321:1218). However, while ESCs are generated from the inner cell mass of a blastocyst, iPSCs can be generated from somatic cells (e.g., skin-derived fibroblasts) of an adult and induced to pluripotency by in vitro genetic manipulation. Efforts to optimize the induction process are ongoing and include eliminating viral integration (Stadtfeld et al., 2008, Science 322:945) or replacing genetic induction with chemical/growth factor induction. Although there are known differences between iPSCs and ESCs, the ability of iPSCs to generate neural cell types makes it a useful tool to study cellular mechanisms underlying human development and disease. Additionally, similar methods have been used to transdifferentiate adult cells to induced neuronal cells (iNCs), which bypass the pluripotent stage of iPSCs to generate neurons (Vierbuchen et al., 2010, Nature 463:1035). Yet another method, involving the generation of neural stem cells from patient olfactory epithelium, has been used to compare cellular differences between psychiatric patients and control subjects (reviewed in Cascella et al., 2007, J. Neurochem. 102:587). The relatively easy access of source tissue means that human iPSCs and iNCs hold promise for elucidating patient-specific cell dysfunction or response to candidate therapeutics.
Realization of the full potential of these tools and technologies for accelerating discoveries in mental disorders will require the free and open sharing of cellular material with associated phenotypic and genotypic data among researchers. For mental disorders and other complex diseases, sharing is often absolutely necessary to achieve sample sizes that have adequate statistical power for detecting subtle phenotypic differences. Other specific scientific advantages of sharing research resources include facilitating the rapid replication of new findings, stimulating multidisciplinary translational research programs that include clinical and basic scientists, providing needed resources to promising young investigators, avoiding duplicative data collection efforts and laboratory work, and facilitating the rapid application of state-of-the-art technologies and analytic methods to human data sets. These advantages are expected to facilitate our understanding of pathophysiology, and accelerate the development of new therapeutic compounds and diagnostic tests.
In order to continue to enhance and enrich research resources for open sharing with the scientific community, NIMH plans to fund one repository for human control and patient-derived cells and their reprogrammed derivatives to support stem cell research relevant to mental disorders under this Notice. The long-term objective of research resource enrichment under this Notice is to accelerate molecular, cellular, and developmental biological discovery in mental disorders.
Scope and Objectives
The intent of this Notice is to seek applications for and support one repository/resource for postnatal-to-adult human control and patient-derived cells and their reprogrammed derivatives; this repository will support stem cell research relevant to mental disorders. This includes but is not limited to anxiety disorders, attention deficit hyperactivity disorder, autism spectrum disorders, bipolar disorder, borderline personality disorder, depression, eating disorders, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and schizophrenia. The capabilities of the repository will range from derivation and banking of primary source cells from postnatal through adult human subject tissue to more comprehensive banking and validation of iPSCs or similar reprogrammed/de-differentiated cells. This initiative will not support the resourcing of biological materials from germline or prenatal sources such as human ESCs or somatic cell nuclear transfer (SCNT).
The repository funded under this Notice will be directed by a Principal Investigator (PI), and will receive guidance from NIMH program staff to assist with identification and implementation of appropriate strategies and priorities. It is expected that the repository will be staffed by an integrated team of investigators (within a single institution or across institutions) with expertise in patient sample collection, cellular and molecular biology. This effort may involve activities at multiple institutions that are strategically and functionally coordinated such that the repository will function as a single, national resource.
Given that design of studies using patient-derived and control stem cells such as iPSCs is increasingly done in the context of gene variants associated with particular disorders, a critical feature of the repository will be integration of data from source cells and induced derivatives with genetic and phenotypic data collected from the same subjects, that will facilitate current and future discoveries in the biology of mental disorders. Thus, a critical feature of the repository is that it will be integrated into the NIMH Center for Collaborative Genetic Studies on Mental Disorders (http://zork.wustl.edu/nimh/home/NIMH_Gen_Initiative.html), which currently provides bioinformatics infrastructure to support current and future discoveries in the genetics of mental disorders. The repository personnel must be able to effectively interface with personnel in computer and information sciences, statistical genetics and psychiatric genetics; this will enable the cyberinfrastructure to integrate relevant and often disparate resources to provide a broad-access and enabling framework for human biological research in mental disorders.
It is expected that the principal investigator and the proposed team have direct experience in providing to the scientific community research resources and services for stem cell studies, as well as experience in interacting with a cyberinfrastructure for a mature scientific discipline. Successful proposals will demonstrate exceptional and transparent quality control, quality assurance and standard operating procedures, exceptional facilities and infrastructure for inventory and database management, storage, and distribution of viable biologicals as well as procedures for adherence to all NIH rules and guidance regarding informed consent and tissue acquisition. Specific areas of scientific expertise required by the repository/resource are:
Specific functions and services to be performed by the repository for the scientific community are:
These services and research resources will be provided to the scientific community by the repository on a fee-for-service basis. Fees charged will recover costs and service delivery costs. Applications in response to this Notice should include detailed plans for the advisory, research and development, and other fee-for-service functions of the repository.
This notice calls for competitive revision applications to active NIH Research Grants funded under the U24 grant mechanism.
To be eligible, the “parent” award on which the revision application is based must be active at the time the revision application is submitted. The project period of the competitive revision may not extend beyond that of the “parent” award. If a no-cost extension is needed to complete the work to be proposed in the revision, the no-cost extension must be in place before the application is submitted.
The proposed studies must be within the scope described in the “Scope and Objectives” section above.
For all revision applications, the Project Director/Principal Investigator (PD/PI) must be the same as the PD/PI on the parent award. For revision applications to multiple PD/PI parent awards, the Contact PD/PI must be the PD/PI listed on the parent application. A competitive revision does not allow a change in the Multiple PD/PI team nor a conversion from a single PD/PI to multiple PD/PIs.
All revision applications must be submitted by the sponsoring institution of the PD/PI (or Contact PD/PI for multi-PD/PI grants) listed on the parent grant. Only one revision request may be submitted per PD/PI of an NIH-funded parent project.
NIH encourages the participation of individuals from racial and ethnic groups underrepresented in biomedical and behavioral research, individuals with disabilities and individuals from disadvantaged backgrounds.
Budget and Funding Information
The NIMH intends to commit up to $1.5 million in total costs per year beginning in FY2011 for up to three years, with an expected duration not to exceed that of the parent award budget period. The scope and budget of the requested revision must reflect aims and goals that can be accomplished within that timeframe. NIMH intends to fund one award under this Notice.
Applicants must submit a budget using the same budget format as was used for the parent award. Facilities and Administrative (F&A) costs will be paid at the full, negotiated rate. Applicants should provide a detailed budget justification for personnel costs, supplies, and other expenses.
Although the budget plans of the NIMH provide support for this program, awards pursuant to this solicitation are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.
Application Review Process
Applications that are complete and responsive to the Notice will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIMH in accordance with the review criteria stated below.
As part of the initial merit review, all applications will:
The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support 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 standard review criteria, and additional review criteria (as applicable for the project proposed). The review committee will consider the overall scientific merit of the new work proposed, the appropriateness of the match between the parent project and the proposed work, and the likelihood for the project to achieve the goal of the Notice.
Scored Review Criteria.
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? If the aims of the application are achieved, research resources for stem cell studies are freely shared with the scientific community and a cyberinfrastructure established to integrate relevant and often disparate resources to provide an enabling framework for stem cell research, how will knowledge on the molecular, cellular and developmental basis of mental disorders be advanced?
Investigators: Are the PD/PIs, 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 or training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or mulit-PD/PI, do the investigators have complementary and integrated expertise, are their leadership approach, governance and organizational structure appropriate for the project? Does the PD/PI have demonstrated experience in providing high-quality research resources and services for stem cell studies on mental disorders to the scientific community? Is the PD/PI highly committed to the principals of free and open sharing of research resources for stem cell studies of mental disorders?
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? Alternatively, does the project employ novel concepts, approaches, or methods for the production and sharing of research resources and for the development of infrastructure useful to the scientific community?
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? Will the infrastructure developed by the repository succeed in accelerating the discovery of molecular, cellular and developmental processes producing vulnerability to mental disorders? Does the applicant utilize state-of-the-art methods to create an efficient infrastructure? Does the investigator utilize appropriate molecular and cellular biological techniques to assure a high rate of success (98% or greater) in establishing non-reprogrammed cell lines from both domestic and foreign sites? Does the investigator utilize sound approaches for quality control and validation of critical properties of banked cells that ensure their usefulness to the research community? Does the proposal provide for transparency in standard operating procedures and other components necessary to facilitate stem cell research relevant to mental disorders?
Environment: Will 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?
Additional Review Criteria. As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items: Protections for Human Subjects; Inclusion of Women, Children, and Minorities; Vertebrate Animals; and Biohazards
Additional Review Considerations. As applicable for the project proposed, reviewers will address 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: Budget and Period Support; Select Agent Research. In addition, reviewers will assess the reasonableness of the resource and data sharing plans.
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 NIH eRA Commons.
The following will be considered in making funding decisions:
If the application is considered for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General. A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.
Terms of Award
All awards will be subject to the standard NIH terms of award. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Section IV.5., “Funding Restrictions.”
This award will adhere to the terms and conditions of the funding opportunity announcement RFA-MH-08-100 Section VI. Specifically, a Program Official from the participating NIH Institute or Center will be assigned to the funded application and will assume responsibility for normal stewardship of the award. Coordination of the repository’s activities will be accomplished through close collaboration between the repository scientific staff, NIH program staff, and a scientific steering committee currently providing scientific oversight to the NIMH Center for Collaborative Genetic Studies on Mental Disorders.
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.
How to Apply
The receipt date for revision applications is September 25, 2010 (Changed to September 24, 2010 per NOT-MH-10-032).
Applicants interested in applying for revision support must submit the application through Grants.gov, using the Funding Opportunity Announcement (FOA) that was used for the parent grant. Or, if this FOA is no longer active, use the Parent FOA that matches the program (activity code) of the award.
For ALL applications:
Follow the instructions as noted below. Note: Font size restrictions apply as designated within the applicable SF424 (R&R) Application or the PHS398 application instructions. The current NIH guideline on page limitations should be followed.
a) Specific Aims. Summarize the activities that were included in the “parent” grant that encompass those proposed in the revision request. This section should include a description of the revision’s specific aims, including design and methods for resource and data management and distribution. Describe the relationship of the revision request to the “parent” grant and the impact that the proposed work will have on the research field(s) involved.
b) Research Strategy. The research strategy section, limited to 12 pages, should discuss how the expertise and the existing research resources from the current parent grant can be leveraged and synergized with the expertise of the NIMH Center for Collaborative Genetic Studies on Mental Disorders to facilitate the resourcing of cell lines and associated data to the scientific community to support stem cell studies relevant to mental disorders..
c) Budget. The budget format of the competitive revision must be the same as that of the “parent” application, with a justification that details the items requested, including Facilities and Administrative costs and a justification for all personnel and their role in this project.
d) Biographical Sketch for PD/PI and all new Senior/Key Personnel. (those who are additions on the revision project). You will need to include an updated biographical Sketch for the PD/PI and new Senior/Key Personnel, using the forms, which are available as MS Word (http://grants.nih.gov/grants/funding/phs398/biosketch.doc) or PDF (http://grants.nih.gov/grants/funding/phs398/biosketch.pdf). There is no need to repeat information previously provided for other Senior/Key Personnel.
e) Human Subjects/Vertebrate Animal documentation (as applicable). Include a current Human Subjects/IRB or Vertebrate Animals/IACUC approval letter, if available. Otherwise, this will be required at the time of funding. All appropriate IRB and IACUC approvals must be in place prior to a revision award being made. Any differences in the involvement or use of human subjects or specimens, or use of vertebrate animals, between the administrative revision activity and the parent grant should be noted. When appropriate, details should be provided on the protection of human subjects and inclusion of women, children, and minorities. Additional guidance on Human Subjects Research and Vertebrate Animals is provided under Part II of the PHS 398 instructions (http://grants1.nih.gov/grants/funding/phs398/phs398.html).
For electronic applications (R01, R37): Use the SF424 (R&R) Application Guide available at: http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_Adobe_VerB.doc (MS Word [3.5 MB]) or http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_Adobe_VerB.pdf (PDF [4.5 MB]).
f) Plan for Sharing Research Resources and Data
NIH policy expects that award 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). The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing.
Resource sharing with the scientific community is integral to the purpose of this Notice. The reasonableness of the data sharing components of the Plan will also be assessed by the reviewers; however, since data sharing will depend on post-award integration with the cyberinfrastructure of the current NIMH Center for Collaborative Genetic Studies on Mental Disorders with oversight of its steering committee, reviewers will not factor the proposed data sharing elements into the determination of scientific merit or the impact/priority score.
The sharing of biomaterials and data in a timely manner has been an essential element in the rapid progress that has been made in the analysis of human diseases. To address the joint interests of the government in the availability of, and access to, the results of publicly funded research and in the opportunity for economic development based on these results, NIH requires applicants who respond to this Notice to develop and propose detailed plans for data sharing. It is expected that data sharing plans minimally include all phenotypic and genotypic data. All data and biomaterials managed and produced by the Center are required to be widely distributed to the national and international scientific community.
It is expected that the investigator's sharing plan will include the following elements: (1) comprehensive and verified databases that contain all clinical, diagnostic, and genotypic information; (2) high-quality cell lines which are appropriate for stem cell research relevant to mental disorders; (3) mechanisms by which all databases and any biomaterials are widely distributed to qualified investigators in the scientific community; (4) a protocol for wide dissemination of these data and applicable biomaterials; (5) a timetable for distribution; and (6) an assurance that data and applicable biomaterials are disseminated in a manner comparable to pre-existing protocols and procedures for distributing such data and biomaterials in the NIMH Human Genetics Initiative (see http://nimhgenetics.org).
The timeline for data sharing is evolving, and expectations for rapid data sharing are increasing. It is expected that all data will be released to the scientific community no later than the end of the award period, even if a competing renewal application is submitted. More rapid sharing, i.e., at quarterly intervals during the award period, is strongly encouraged.
NIMH, in consultation with NIH's Office of the General Counsel, the National Human Genome Research Institute's Ethical, Legal, and Social Implications Research Program and the Department of Health and Human Services' Office for Human Research Protections, has developed a model consent form for use in human genetic research at http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html. This may then serve as a template that is subject to modification and/or approval by local institutional review boards. NIMH will review consent forms and IRB approvals for all projects prior to funding under this Notice. It is expected that the applicant's approved consent form address the following:
The adequacy of the Resource and Data Sharing Plan will be considered by Program staff of the funding organization when making recommendations about funding applications; it will also be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.
The repository funded under this Notice will facilitate and accelerate free and open sharing among researchers in the scientific community by providing cell lines and associated electronic datafiles for the genetic, molecular, cellular and developmental analysis of mental disorders.
Applicants are strongly encouraged to discuss their plans for responding to this Notice by contacting the NIMH Program Director listed below. Scientific inquiries can also be directed to the NIH Program Directors who oversee the parent grant associated with the competitive revision request.
David M. Panchision, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7186, MSC 9641
Bethesda, MD 20892-9641
Telephone: (301) 443-5288
FAX: (301) 451-5615
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