NEUROPROTECTIVE CNS BARRIERS IN NEUROLOGICAL DISEASES
|RELEASE DATE:August 28, 2003
EXPIRATION DATE:May 1, 2006, unless reissued
COMPONENTS OF PARTICIPATING ORGANIZATIONS:
National Institutes of Health (NIH):http://www.nih.gov/
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Mental Health (NIMH):http://www.nimh.nih.gov/
National Institute on Aging (NIA):http://www.nia.nih.gov/
Department of Health and Human Services (DHHS)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):93.853 (NINDS), 93.242 (NIMH), 93.866 (NIA)
THIS PA CONTAINS THE FOLLOWING INFORMATION:
- Purpose of the PA
- Research ObjectivesMechanism(s) of Support
- Funds Available
- Eligible Institutions
- Individuals Eligible to Become Principal Investigators
- Where to Send Inquiries
- Submitting an Application
- Peer Review Process
- Review Criteria
- Award Criteria
- Required Federal Citations
PURPOSE OF THE PA:
The goal of this Program Announcement with set-aside funds (PAS) is to invite applications for studying the neurobiological and cerebrovascular mechanisms through which the neuroprotective blood-brain and blood-csf barriers function in the healthy and diseased adult, aged and pediatric brain. Blood-Brain Barrier (BBB) research embodies the true meaning of a “translational model” of neuroscience wherein breakthroughs in basic neuroscience are delivered to the clinic and require an agent delivery strategy and/or the ability to target specific areas of the brain. This PAS encourages studies focused on improving our understanding of the neuroprotective CNS barriers and enhancing the effectiveness of drug and gene delivery strategies for treatment of neurological diseases. Chief among the challenges to be addressed is the need to increase our knowledge about the molecular and cellular biology, cells of origin, gene and protein expression, and the regional differences of brain microvascular endothelial cells and pericytes and their interactions with adjacent brain cells.
A major challenge for treatment of most brain disorders is overcoming the difficulty of delivering therapeutic agents to specific regions of the brain. In its neuroprotective role, the blood-brain barrier (BBB) functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the BBB into the brain in adequate amounts. Improving our knowledge of the molecular and cellular biology of the brain microvasculature and their interactions with surrounding brain cells, which constitutes the BBB in vivo, could lead to innovative strategies for drug and gene targeting to injured or disease tissue. Also, research is needed on the role of the brain microvasculature in protecting the brain from toxic agents and how damage to the BBB leads to long-term neurological toxicity in the development of many neurological diseases. Understanding the basic biology of how the BBB works under normal and disease conditions across the lifespan may also provide insight on the integrative function of the brain. Research focused on cerebrovascular endothelial cell biology may provide insight into the “neurovascular unit”, a conceptual model that considers brain function from the perspective of interactions among blood cells, endothelium, glia, pericytes, extracellular matrix and neurons.
This initiative was identified as the top research priority of the Brain Tumor Progress Review Group (PRG). The Stroke Progress Review Group has also identified neurovascular research and BBB biology as a high priority for advancing our understanding of stroke and brain function. Both Progress Review Groups are responsive to Congressional requests for planning in these areas. Also, the NINDS Neuroscience at the New Millennium Plan clearly identifies research on the blood-brain barrier as a scientific priority. The scientific support for this initiative can be found in these reports on the NINDS homepage at:
This Program announcement is intended to achieve a better understanding of the effects of neurological disorders on the blood-brain barrier (BBB), improve our knowledge of BBB biology and how it may contribute to the initiation and/or progression of neurological disease over the lifespan and develop new approaches for targeting the BBB, based on biological considerations, in order to improve drug delivery and target treatment of one or more such disorders.
Applications that address gene and protein expression for microvascular endothelial cells within normal, aging, and diseased brain such as gliomas or the ischemic penumbra are encouraged. Cerebrovascular genomics is considered a high priority. Because only very abundant BBB-specific transcripts will be detected with whole-brain gene microarrays, cerebrovascular genomics research needs to start with the initial isolation of brain capillaries from animal or human brain, both normal and perturbed. Comparison of capillaries from normal brain and perturbed tissue can help to elucidate the tissue-specific gene expression. Pattern-specific tissue expression could provide the platform for further investigations on overall brain vascular biology as it pertains to conditions such as angiogenesis, cell adhesion, antigen presentation, metastasis, cell-cell communication and local inflammation.
There are several modalities for drug and gene delivery through the BBB. They include: BBB disruption; the use of endogenous transport systems, including carrier-mediated transporters such as glucose and amino acid carriers; receptor-mediated transcytosis, systems such as the insulin or transferrin receptor; and active efflux transporters such as p-glycoprotein and the associated anti-porters. Studies to determine which strategies are most effective and how they can be improved for patients with neurological diseases are encouraged.
Research areas appropriate for this announcement include, but are not limited by the following examples:
- Develop and characterize in vivo and in vitro models that reflect the unique features of the BBB as translational models of neurological disease. Existing in-vivo models, such as those for stroke or lysosomal storage diseases, may also prove useful for studying the structure and dynamics of the BBB. Studies that validate in vitro results with in vivo models are encouraged.
- Examination of the genes and proteins that are uniquely expressed by the intact BBB and mechanisms by which brain cells regulate endothelial cell gene expression. This includes changes that occur in response to neurological disease or the aging process, for example, characterization of molecular signatures for disease diagnosis and targeting.
- Explore the genesis and regulation of the BBB, its stem cell origins and remodeling of the (diseased/damaged/aged) brain microvasculature.
- Identify signal transduction pathways of brain capillary endothelial transcytosis and tight junction regulation under normal and disease conditions.
- Characterize endogenous influx and efflux properties of the barriers including transporters in luminal and abluminal membranes of brain endothelium and epithelium.
- Identify regional diversity of barrier properties within the brain and spinal cord microvasculature.
- Characterize brain endothelial tight junction proteins in normal and disease states.
- Investigate the various enzymatic barrier mechanisms.
- Characterize membrane protein expression by cells of the BBB.
- Development of novel brain drug and gene delivery methods based on unique properties of the BBB including gene therapy via vectors or via modified autologous cell transfer.
- Explore the molecular basis of microbial interactions with brain endothelium.
- Develop neuroimaging tools to identify changes in BBB permeability in vivo.
- Examination of the molecular and cellular mechanisms of leukocyte migration at the BBB throughout the lifespan.
- Comparison of transport systems in brain endothelia with choroids plexus epithelium as well as systemic epithelial cells.
- Explore the interactions among the cellular and matrix elements of the BBB, for example, the microvascular basement membrane.
- Examine the plasticity of the blood-brain and blood-CSF interfaces throughout the lifespan.
Applications should focus on neurological disorders relevant to the research missions of NINDS, NIMH and/or NIA. A partial list of diseases of interest to NINDS is given in Appendix A of the planning document Neuroscience at the New Millennium. These include neurological disorders (e.g. stroke, brain tumors, Parkinson’s disease, brain and spinal cord trauma, epilepsy, multiple sclerosis, brain lysosomal storage disorders, neuro-AIDS and Alzheimer’s disease). The NIMH is interested in mechanistic studies of trafficking of cells, immune molecules and drugs across the blood-brain and blood-csf barriers during development and adulthood and how these processes impact the pathogenesis of neuroAIDS and mental disorders.
NIA is interested in age-related neurodegenerative disorders, such as Alzheimer’s disease, brain injury, and impairments in cognitive, motor and sensory functions.
MECHANISMS OF SUPPORT:
A large amount of basic research is needed to significantly change how we translate neuroscience research bidirectionally. This PAS is focused on stimulating new concepts in the BBB field through the exploratory/developmental grant (R21) and the R01 mechanisms. The current workforce in the BBB field is small relative to the scientific and clinical needs for improved understanding of the BBB and progress will require collaboration among current investigators and scientists from disciplines not currently working in this area. Therefore, training and early career development will be encouraged (please contact Program Staff for additional information). This PAS will remain active for 3 years to address the many gaps in our knowledge of how the neuroprotective barriers function and the time needed to increase the workforce in this critically important translational research area.
As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Applicants are encouraged to contact program staff for advice about choosing the appropriate grant mechanism.
The R21 mechanism (see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) is intended to encourage new exploratory/developmental research projects by providing support for the early stages of their development. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models or applications that could have major impact on a field of biomedical, behavioral, or clinical research.
Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or
R21 applications may request a project period of up to two years with a combined budget for direct costs of up $275,000 for the two-year period. For example, you may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of your project. Normally, no more than $200,000 may be requested in any single year.
This PAS uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting 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. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement athttp://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.
Competing continuation applications submitted in response to this PA will compete with all investigator-initiated applications and be referred and reviewed according to the customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The earliest anticipated award date is June 1, 2004.
NINDS, NIMH, and NIA have set aside $2,000,000 in total costs per year, in addition to funds available for applications sent in response to this program announcement that score within the NINDS payline (see NINDS Funding Strategy http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm), depending on the overall scientific merit of the applications and the availability of funds throughout the duration of this solicitation (3 years). Applications submitted in response to this PA will compete with all investigator-initiated applications for funding.
The total project period for an application submitted in response to this PA may not exceed 5 years. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the Institute provide support for this program, awards pursuant to this PA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.
You may submit (an) application(s) if your institution has any of the following characteristics:
- For-profit or non-profit organizations
- Public or private institutions, such as universities, colleges, hospitals, and laboratories
- Units of State and local governments
- Eligible agencies of the Federal government
- Domestic or foreign institutions/organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS:
Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.
WHERE TO SEND INQUIRIES:
We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues:
Direct inquiries regarding scientific/research issues to:
|Dr. Thomas P. Jacobs
Neuroscience Center, Rm 2112
6001 Executive Blvd.
Bethesda, MD 20892-9527
Telephone: (301) 496-1431
FAX: (301) 480-2424
|Dr. Bradley C. Wise
National Institute on Aging
7201 Wisconsin Avenue, Suite 350
Bethesda, MD 20892-9205
Telephone: (301) 496-9350
FAX: (301) 496-1494
|Dr. Jeymohan Joseph
Neuroscience Center, Rm 6202
6001 Executive Blvd.
Bethesda, MD 20892-9527
Telephone: (301) 443-3012
FAX: (301) 443-9719
Direct inquiries regarding financial or grants management matters to:
|Ms. Tina Carlisle
Grants Management Branch
6001 Executive Boulevard, Rm
Bethesda, MD 20892
Telephone: (301) 496-3938
|Ms. Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212
Bethesda, MD 20892-9205
Telephone: (301) 496-1472
FAX: (301) 402-3672
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-0004
FAX: (301) 443-0219
SUBMITTING AN APPLICATION:
Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at
. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at
in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email:
APPLICATION RECEIPT DATES:
Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. Please note that AIDS related applications have separate receipt dates.
All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions:
- Research PlanFor R21 applications only, items a ? d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required for R21 proposals, but may be included if it is available. Please note that a Progress Report is not needed for R21 awards; competing continuation applications for an exploratory/developmental grant will not be accepted.
Appendix. Use the instructions for the appendix detailed in the PHS 398 except that for R21 applications, no more than 5 manuscripts, previously accepted for publication, may be included.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:
Applications requesting up to $250,000 per year in direct costs must be submitted in the modular grant format. The modular grant 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 (rev. 5/2001) at
includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at
SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:
Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application.
Applicants requesting more than $500,000 must carry out the following steps:
- Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study;
- Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and,
- Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application.
This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 athttp://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.
SENDING AN APPLICATION TO THE NIH:
Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
Applications must be received by or mailed on or before the receipt dates described athttp://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR 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 unfunded version of an application already reviewed, but such application must include an Introduction addressing the previous critique.
Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks.
PEER REVIEW PROCESS:
Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit.
As part of the initial merit review, all applications will:
- Undergo a 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
- Receive a written critique
- Receive a second level review by the appropriate national advisory council or board
The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application.
The 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.
- SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field?
- APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics?
- INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies?
- INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)?
- ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support?
ADDITIONAL REVIEW CRITERIA:
In addition to the above criteria, your application will also be reviewed with respect to the following:
PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application.
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below).
ADDITIONAL REVIEW CONSIDERATIONS:
SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score.
BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research.
Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:
- Scientific merit of the proposed project as determined by peer review
- Availability of funds
- Relevance to program priorities
REQUIRED FEDERAL CITATIONS:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998.
Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the “Standards for Privacy of Individually Identifiable Health Information”, the “Privacy Rule,” on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights(OCR). Those who must comply with the Privacy Rule (classified under the Rule as “covered entities”) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply).
Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on “Am I a covered entity?” Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found athttp://grants.nih.gov/grants/guide/notice files/NOT-OD-03-025.html.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of “Healthy People 2010,” a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of “Healthy People 2010” athttp://www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found athttp://grants.nih.gov/grants/policy/policy.htm.
The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.