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NINDS Advisory Council Meeting Minutes, February 6-7, 2003

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Department of Health and Human Services
Public Health Service
National Institutes of Health
National Advisory Neurological Disorders and Stroke Council

Summary of Meeting1
February 6-7, 2003

The National Advisory Neurological Disorders and Stroke (NANDS) Council was convened for its 156th meeting on February 6-7, 2003, in Building 1, Wilson Hall, National Institutes of Health, Bethesda, Maryland. Dr. Audrey Penn, Acting Director of the National Institute of Neurological Disorders and Stroke (NINDS), served as Chairperson.

In accordance with Public Law 92-463, the meeting was:

Open: February 6, 2003 --10:30 a.m. to 5:00 p.m.

for the review and discussion of program development, needs, and policy; and

Closed: February 6, 2003 - 5:00 p.m. to 5:55 p.m.
February 7, 2003 - 8:00 a.m. to 10:20 a.m.

for the review of the Board of Scientific Counselors' Reports and discussion and consideration of individual grant applications.

Council members present were:

Mr. Ronald Bartek
Dr. Bruce Bean
Ms. Jeanne Carpenter (2/6 only)
Dr. J. Donald Easton
Dr. Apostolos Georgopoulos
Dr. Daniel Lowenstein
Dr. Peter MacLeish
Mr. Brad Margus
Mr. Jeffrey Martin
Ms. Ellyn Phillips
Dr. Joshua Sanes
Dr. Sally Shaywitz
Dr. Ira Shoulson
Dr. Lydia Villa-Komaroff
Mr. Robert Waterman

Council members absent were:

Dr. Keith Black
Dr. John Griffin
Dr. Susan Hockfield

Council Roster (Attachment 1)

Ex Officio Members present:

Dr. Paul Hoffman, Department of Veterans Affairs

Dr. Geoffrey Ling, Department of Defense (2/6 only)

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Members of the public present for portions of the open meeting included:

Dr. Dietrich Stephan, Children's National Medical Center
Ms. Sarah Brantigam, Children's National Medical Center
Ms. Cara Schmitt, Epilepsy Foundation
Dr. Perry Cohen, PDF
Mr. Robert Balkam, Restless Leg Syndrome Foundation

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NINDS employees present for portions of the meeting included:

Dr. Audrey S. Penn
Dr. Constance Atwell
Dr. Paul Nichols
Dr. Robert Baughman
Dr. Eugene Oliver
Dr. Alan Willard
Dr. Arlene Chiu
Dr. Toby Behar
Dr. Emmeline Edwards
Ms. Cikena Reid
Ms. Lynn Morin
Dr. John Marler
Dr. Claudia Moy
Dr. Raul Saavedra
Ms. Marian Emr
Dr. Scott Janis
Dr. Naomi Kleitman
Ms. Quandra Scudder
Dr. Story Landis
Dr. Thomas Miller
Dr. Ursula Utz
Ms. Nena Wells
Ms. Susan Free
Ms. Marvene Horwitz
Ms. Gladys Bohler
Dr. Eugene Major
Dr. Joanne Odenkirchen
Mr. Michael Loewe
Dr. Ronnie Horner
Ms. Christina King
Ms. Debbie Jarman
Ms. Sue Titman
Ms. Song West
Ms. Margo Warren
Ms. Rebecca Farkas
Mr. George Bramhall
Ms. Peggy Whittington
Dr. Cynthia McCormick
Dr. Linda Porter
Dr. JoAnn McConnell
Mr. Robert Loughlin
Dr. Barbara Radziszewska
Ms. Janice Cordell
Dr. Katherine Woodbury Harris
Ms. Tania Zeigler
Dr. Paul Sheehy
Ms. Ruth Linn
Mr. Andy Baldus
Dr. Robert Zalutsky
Mr. Paul Girolami
Dr. Diane Murphy
Dr. Henry Khachaturian
Dr. Deborah Hirtz
Ms. Sylvia Parsons
Dr. Tom Jacobs
Dr. Yuan Liu
Dr. Meenaxi Hiremath
Dr. Ernest Lyons
Dr. Bernard Ravina
Dr. Katrina Gwinn-Hardy
Ms. Liz Geiger
Ms. Margaret Jacobs
Mr. Levon Parker
Ms. Carol Rowan
Mr. Paul Myers
Dr. Susan Daniels
Dr. Gabriel Leblanc
Ms. Maureen Hambrecht
Dr. Robert Finkelstein
Ms. Stephanie Clipper
Dr. Frances Yee
Dr. Daofen Chen
Dr. Diane Lawrence
Mr. James Stable
Dr. Steven Warach
Dr. Michael Rogawski
Dr. Mary Mouradian
Dr. John Hallenbeck
Dr. Sussan Paydar
Dr. Maureen Beanan
Dr. Som Rao
Dr. Usha Gante
Ms. Shannon Garnett
Ms. Janette VanMeers
Dr. Laura Mamounous
Ms. Lorraine Fitzsimmons
Ms. Adrienne Marshall
Ms. Denise Chatman
Dr. Peter Gilbert
Dr. Merrill Mitler

Other Federal employees present for portions of the meeting included:

Dr. Doug Anderson, Department of Veterans Affairs
Dr. Adam Richman, Department of Veterans Affairs
Dr. William Benzing, CSR
Dr. Christine Melchior, CSR
Dr. Gillian Einstein, CSR
Dr. David Armstrong, CSR
Dr. Betsy Ra, CSR
Dr. Brent Stanfield, CSR
Dr. Karl Malik, CSR
Dr. Donald Schneider, CSR
Dr. Michael Lang, CSR
Dr. Anita Miller Sostek, CSR
Dr. Sherry Stuesse, CSR
Dr. John Fakunding, NHLBI

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I. Call to Order and Opening Remarks

Dr. Audrey Penn, Acting Director, NINDS, welcomed Council members, guests and staff to the 156th Council meeting and made the following announcements regarding Council members: Dr. Daniel Lowenstein has taken a position at the University of California, San Francisco, Dr. Lydia Villa-Komaroff has recently been named Vice President for Research and C.E.O. at the Whitehead Institute, and Brad Margus has been asked to join the HHS Secretary's Advisory Committee on Genetics, Health, and Society. Absent are Dr. Susan Hockfield, who has recently been named Provost of Yale University; Dr. Keith Black, and Dr. Jack Griffin, who is not here today but will attend tomorrow.

In staff news, Dr. Story Landis, Director of the Division of Intramural Research, has been elected President of the Society for Neuroscience; Dr. William Heetderks has taken the position of Associate Director for Extramural Research at the National Institute of Biomedical Imaging and Bioengineering; Dr. Giovanna Spinella has taken a similar role at the Office of Rare Diseases. New staff in the Office of Policy and Planning are Dr. Heather Rieff, science policy analyst; and Dr. Rebecca Farkas, AAAS-NIH Science Policy Fellow.

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II. Report of the Associate Director for Extramural Research

Government in the Sunshine Act and the Federal Advisory Committee Act

Dr. Constance Atwell, Associate Director for Extramural Research, NINDS, reviewed the Government in the Sunshine Act and the Federal Advisory Committee Act, which require the Department of Health and Human Services to open to public observation as many advisory committee meetings as possible, including the National Advisory Council's. The NANDS Council meeting was open to the public, except during the review of the Board of Scientific Counselors' Reports and the review of grant applications. Notice of the date and place for the Council meeting was published in the Federal Register thirty days prior to the meeting.

Conflict of Interest

The regulations concerning conflict of interest were reviewed. Council members were reminded that materials furnished for review purposes and discussion during the closed portions of the meeting are considered privileged information. All Council members present signed a statement certifying that they did not participate in the discussion of, or vote on, an application from any organization, institution, or any part of a university system, of which they are an employee, consultant, officer, director or trustee, or in which they have a financial interest. Institutions or organizations which have multi-campus institution waivers, or are specifically designated as separate organizations under 18 U.S.C. 208(a), are exempt from this provision.

Confidentiality

During the closed session, any information that is discussed and the outcome of any recommendation are considered privileged information. They may not be discussed outside of the closed session. If an applicant requests support for his or her application from a Council member, the Council member must respond that he/she is not permitted to discuss the application. Any inquiry should be referred to Dr. Constance Atwell as Council Executive Secretary, who will then refer the questions to the appropriate staff member for response.

Consideration of Minutes of Previous Council Meeting

The minutes of the Council meeting of September 12-13, 2002, were considered and accepted as written.

Consideration of Dates for Future Council Meetings

The following dates for future Council meetings were reconfirmed:

  • May 22-23, 2003 (Thursday and Friday)
  • September 18-19, 2003 (Thursday and Friday)
  • February 12-13, 2004 (Thursday and Friday)
  • May 27-28, 2004 (Thursday and Friday)
  • September 9-10, 2004 (Thursday and Friday)

New Dates

  • February 10-11, 2005 (Thursday and Friday)
  • May 26-27, 2005 (Thursday and Friday)
  • September 15-16, 2005 (Thursday and Friday)
Other Items
  • Council General Recommendations
    Dr. Atwell described proposed changes to the Council General Recommendations. These are the general guidelines for administrative actions that may be taken by program staff without prior approval by Council. Two minor editorial changes have been proposed. No changes in policy. A motion was made and seconded to approve the changes in the Council General Recommendations. A copy of the approved Council General Recommendations is attached as Appendix 1.

  • Inclusion of Women and Minorities as Subjects in Clinical Research
    Council is required every two years to review the NINDS part of the NIH report for tracking the inclusion of women and minorities as subjects in clinical research. The Council members had received in advance of the meeting materials that described how NINDS in particular has implemented the policy on appropriate inclusion of women and minorities in clinical research. They were also provided with the website for the full report entitled "Monitoring Adherence to the NIH Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research."

    Dr. Mary Ellen Michel reported on several new reporting requirements. The first is that Phase III clinical trials grantees are now allowed inclusion of written statements about differences in treatment between males and females and in minorities. Another change is the use of OMB guidance to distinguish among Hispanic minorities. The third is a new requirement to track women and minorities by protocol, not by grant. Dr. Michel confirmed that the most recent inclusion data confirm that minorities and women are represented in NINDS-supported research.

  • Reports Book
    The Reports Book consists of applications that have been designated for funding since the last Council meeting. It includes interim actions that have been taken and the status of applications that were identified for High Program Priority. Dr. Atwell encouraged Council to communicate their preferences for funding to the staff.

  • Expedited Review Process
    Council approved 163 applications for expedited payment, and 105 applications have been awarded to date.

  • New Staff
    Dr. Atwell introduced the following new staff to Council: Ms. Janice Cordell, Clinical Research Project Manager, Clinical Trials Cluster; Dr. Michael Nunn, Program Director, Neural Environment Cluster; Dr. Merrill Mitler, Program Director, Systems and Cognitive Neuroscience Cluster; Dr. Robin Conwit, Program Director, Clinical Trials Cluster; Dr. JoAnn McConnell, Scientific Review Administrator, Scientific Review Branch; Dr. Maureen Beanan, Program Analyst, Repair and Plasticity Cluster; Dr. Som Rao, Program Analyst; Office of Technology and Development; and Ms. Usha Ganti, Program Analyst, Office of Minority Health and Research.

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III. Report of the Acting Director, NINDS

  • Budget Overview
    Dr. Audrey Penn, Acting Director, NINDS, presented a table, which listed the budgets of the previous fiscal year (FY02) and both the President's and the Senate's proposed FY03 budgets, for NIH and NINDS. In FY02, NIH's total budget was $23.456 billion, which represented a 14.6% increase over the previous year. The NINDS budget was $1.313 billion, which was a 12.9% increase. There is a revised President's budget for FY03, which proposes over $27 billion for NIH in FY03, a 16.5% increase, and $1.4 billion for NINDS, which is an 8.2 % increase for NINDS. The President's revised budget is currently in a House-Senate conference. The FY04 President's budget requests $27,893 million for NIH, which is a 2% increase over the proposed FY03 budget; and $1.469 million for NINDS, a 3.7% increase. Regarding the question of the payline for FY03, there are several factors that have an impact: the average cost of grants, administrative cuts, the number of applications, the four-year average requirement, and the set-aside budget.

    The FY04 congressional appropriations hearings will be scheduled soon. The I/Cs prepare reports, which are sent to congressional committees through the NIH Director's office, in preparation for the hearings. NINDS filed reports on Parkinson's Disease, Epilepsy, and Muscular Dystrophy.

  • Initiatives
    • The recommendations from the Stroke Progress Review Group are being implemented. A Stroke Working Group has been created from staff across the Extramural Research Division to oversee the implementation.
    • The stewards met recently to continue their oversight of the Epilepsy benchmarks.
    • A Request for Information was issued in December for the Spinal Muscular Atrophy contract. Dr. Kenneth Fischbeck and Dr. William Heetderks conceptualized the SMA project. Once a contract is made, there will be close oversight by an NINDS Steering Group.
    • There have been recent discussions between NINDS staff, Dr. Paul Sheehy in particular, with Dr. Paul Hoffman regarding closer coordination with the V.A. on Amyotrophic Lateral Sclerosis research.
    • The Muscular Dystrophy Task Force, which was organized by NINDS, has met to identify projects that need attention.

  • Porter Neuroscience Center
    Funds have been appropriated to complete the Porter Neuroscience Center. The NIH Director has been very supportive of the Porter Center. Dr. Landis and Dr. Desmond in NIMH are working together on plans for Phase II.

  • Director Search
    The search for an NINDS Director is in the final stages.

    A copy of Dr. Penn's presentation is attached as Appendix 2.

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IV. Report of the Director, NIH

Dr. Elias Zerhouni, Director, NIH, thanked the Council for their service to NIH. There are over 21,000 people who volunteer their time to NIH, and their contributions are highly valued.

Dr. Zerhouni described the central theme around which he has organized his goals for NIH, which he calls the "Roadmap." He began his planning by asking several questions: do changes in either the substance of research or the way in which research is conducted need to be changed; are there systemic roadblocks that need attention; are there knowledge gaps that need to be filled; are all appropriate parties to research being coordinated. After a great deal of input and analysis, three major themes emerged: 1) new pathways to discovery need to be supported, 2) the system of clinical research is at a critical point, and 3) the scientific team of the future needs redefinition. Dr. Zerhouni has encouraged each I/C to develop their own strategic roadmap for each of the thematic categories.

Dr. Zerhouni also discussed the background and development of the new Stem Cell Characterization Facility. A Task Force was formed to address questions about the potential for stem cell characterization and to identify any roadblocks. The Stem Cell Characterization Facility concept was produced as a result of the Task Force recommendations. The Facility will conduct gene expression and analysis; it will not be a repository.

In response to questions from Council members:

  • The Institute director search is his top priority, and he hopes to make a decision very soon.

  • He believes there are enough stem cells available for research; the challenge is to characterize each of them so that they are usable for research.

  • He discussed the need in the U.S. to record, store, and disseminate research data in a more effective way.

  • He agreed that more needs to be done to attract bright young people into a career in biomedical research.

  • In terms of NIH's public health mission, NIH and CDC regularly conduct a burden of disease assessment. He believes more needs to be done to address health disparities.

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V. Update on Fiscal Year 2003 and 2004 Budgets

Dr. Atwell presented FY02, FY03 estimated, and FY03 current budget figures for competing and non-competing budgets. NIH/NINDS has not yet been given a budget for FY03; therefore, we are operating on best estimates. The major impacts on the FY03 competing budget were reviewed, such as the commitments made in FY02 and funds needed for the Porter Neuroscience Building. There is a current estimated budget of $256 million for competing grants. This sum is divided between grants paid on applications that score within the payline, and special initiatives. The current funding strategy includes reducing modular grants by 5% and nonmodular grants by 10%. The total set aside for special initiatives in FY03 has been reduced since the original estimate made last year because some were funded from the FY02 budget. Comparisons in budgets were made between other I/Cs and NINDS. If the actual budget from Congress is significantly less than the Institute's current estimate, the Institute can: 1) reduce the payline, 2) increase the percentage of cuts, or 3) cut awarded grants. The average cost of a grant in FY02 was $369,400. The average so far in FY03 has been $358,400. The lower average cost is due to several factors: 1) cuts made in the grants, 2) the use of lower-cost grant mechanisms (R21), and 3) co-funding of grants by other I/Cs.

There was a discussion about the benefits to maintaining the 23% payline as well as maintaining the percentage of the budget currently designated for special initiatives. Concern was expressed for reducing grants already awarded.

In summary, the Council expressed interest in maintaining the 23% payline and funding strategy. If the actual FY03 budget turns out to be less than the estimate, savings will be found from other budget categories.

Dr. Atwell called the Council's attention to the list of administrative supplements presented in the Reports Book. These are funding programs offered for specific purposes or to augment ongoing research. Council members expressed appreciation for the list of supplements and grantees and requested that supplements information be provided on a routine basis.

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VI. Evaluation of the Reorganization of Neuroscience Review at CSR

Dr. Brent Stanfield, Deputy Director, Center for Scientific Review, presented the history of how the CSR neuroscience review committees were formed and have evolved since they were constituted in 1998. An assessment of the neuroscience review committees began several years later, after allowing time for the study sections to stabilize. Staff, applicants, and members of the extramural research community were consulted, and an internal data analysis was performed. Applicant surveys indicated that applicant satisfaction was strong overall, with the exception of the review of new investigator applications. CSR began its external evaluation utilizing IRG Working Groups in 1998. The goal was to ensure that all applications assigned to IRGs consistently received high-quality review. IRG Working Groups for the reorganized neuroscience study sections met during the summer of 2000. Recommendations made by the Working Groups resulted in corrective actions, such as the creation of a CSR Reviewer Training Committee, the development of an Internet Assisted Review system, the establishment of "Fellowship" study sections, chartering the Neuroscience review committees, and shifting applications among study sections to bring about a more even workload.

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VII. Fiscal Year 2004 Proposed Set Aside Initiatives

Dr. Atwell asked the Council to review for concurrence the initiatives concepts submitted by staff for FY 2004. Under the Federal Advisory Committee Act, all initiatives that involve funding by the federal government must be cleared by an outside review group. The Institute recently decided to ask the NINDS Council to conduct the outside review for all new initiatives. Concurrence does not imply a mandate to go forward, as the final decisions on the initiatives depends on the availability of funds. Since the budget and funding strategy for FY04 have not been determined, dollar amounts are not included with the concepts. Dr. Atwell invited comments from the Council and asked that if Council members have suggestions for new initiatives, to communicate those to staff. Mr. Waterman recommended that research on Restless Leg Syndrome be included in the "Sleep Disorders in Parkinson's Disease and Parkinson's Disease-Like Disorders" RFA. At Dr. Lowenstein's request, several of the program directors described the origin of the initiative concept and the need expressed by the research community. A motion was made and passed by Council approving the concepts.

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VIII. Council Subcommittee Reports

Training and Career Development Subcommittee

Dr. Peter MacLeish, Chair of the Training and Career Development Subcommittee, presented the Neurological Sciences Academic Development Award for Pediatric Researchers program announcement (NSADA-PR). The purpose of the NSADA-PR program is to encourage researchers or medically-trained personnel to go into pediatric research, which is an underserved research area. Trainees may be appointed to the program for three years, and programs are limited to no more than four trainees. The expectation is that the K12 trainee will go on to apply for a K08, K23, or an independent research grant. The original NSADA program announcement, published in 1992, resulted in five grants, supporting thirty trainees. It is too soon to evaluate the results of the first round of the NSADA grants; however, staff is collecting information on papers published, meetings attended, and careers of the trainees following the program. The current version of the NSADA-PR program announcement effectively reduces the number of years an institution can hold the grant from potentially ten years to the standard five-year grant period, and the number of years of appointment for each trainee from five years to three. No trainee may be added to the program after the third year. A question was raised about the need for a similar program to develop researchers in other areas. Dr. Ira Shoulson will investigate this question and report back at the Subcommittee's next meeting.

Clinical Trials Subcommittee

Dr. Daniel Lowenstein, Chair of the Clinical Trials Subcommittee, reported that the Subcommittee discussed four areas: 1) The report from Dr. Scott Janis, Program Analyst for the Clinical Trials group, on the overall function of the Clinical Trials group, from initial contact by a principal investigator to funding of an application. 2) A policy for handling trials that require more time for completion than the length of the initial award. The Subcommittee agreed with a new approach in which an administrative review by a special 3-5 person ad hoc committee would be used when a principal investigator becomes aware that additional time will be needed to complete a study. 3) Reviewed three applications in closed session. 4) Reviewed and discussed the overall portfolio. Mr. Martin asked if data could be collected on recruitment and retention of human subjects in clinical trials. Dr. John Marler, Associate Director, Clinical Trials, stated that collecting that kind of information will be a challenge. NINDS currently funds 1,100 clinical trials, and staff currently track gender and minority data. They will begin collecting recruitment and retention information on the large studies. Council generally expressed its appreciation as well as that of the patient advocacy groups for the Intramural and Extramural clinical trials programs. There are more data available about NINDS-funded clinical trials than ever before. Concern was expressed for the time it takes for a principal investigator to get a clinical trial underway. Dr. Shoulson suggested comparing NINDS clinical trials with other I/Cs and studying ways in which to shorten the process without compromising quality.

Infrastructure, Neuroinformatics, and Computational Neuroscience Subcommittee Report

Dr. Joshua Sanes, Chair of the Infrastructure Subcommittee, related the subcommittee's discussion of three items: 1) Dr. Dietrich Stephan, the principal investigator at the Children's National Medical Center in Washington, D.C., presented a report on the NINDS/NIMH Microarray Consortium. An RFA, issued in 1991, funded three centers; at the University of California, Los Angeles; Duke University; and the Children's National Medical Center. The program is fully operational, with a very impressive website, and has made an encouraging start in terms of grantee response. 2) Dr. Danilo Tagle, Program Director in the Channels, Synapses, and Circuits Cluster, made a presentation on the NINDS workshop, "Proteomics in the Neurosciences," held in December 2002. The Infrastructure Subcommittee suggested that NINDS needs to focus more attention on proteomics and needs to design strategies for encouraging progress in the field. Some ideas discussed were to support centers for mass spectrometric analysis of protein samples, to catalogue existing antibodies' reagents, to fund comparisons of methods for developing new antibodies for large number of proteins of neurological significance, and to develop informatics in proteomics. 3) Dr. Yuan Liu, Program Director in the Channels, Synapses, and Circuits Cluster, discussed a recent planning meeting for a major symposium for BISTI (Biomedical Information, Science and Technology Initiative).

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IX. Overview, Division of Intramural Research

Dr. Story Landis, Director, Division of Intramural Research, reported that the Division is comprised of 64 principal investigators and represents 9% of the NINDS budget. Intramural research ranges from very basic science to clinical trials. The clinical trials include research on Parkinson's disease, multiple sclerosis, and inherited metabolic disorders. Significant effort is being made to explore areas of cooperation with neuroscientists in other NIH Intramural programs, in order to enhance the NINDS research effort, among other benefits. Some examples of these alliances are the formation of an Ion Channel Group, a strong neuro-oncology program, a neuroimaging alliance, and a neurogenetics/neurodegeneration team. Dr. Landis presented examples of Intramural research successes: 1) The finding by Dr. Jeff Diamond that glutamate transporters play an important role in determining the amount of GABA that is synthesized in interneurons. 2) Advances in the area of immunological approaches to stroke damage, which will be presented to Council. 3) Dr. Alan Koretsky's progress in imaging different areas of cortex by distinguishing the Stripe of Gennari and progress in structural imaging. 4) In the area of multiple sclerosis, there are two important new trials underway testing new therapies gauging differences between responders and non-responders to beta-interferon. 5) Dr. Ron McKay's research on neural stem cells and mouse embryonic stem cells.

Porter Building--This project was initially conceptualized by Dr. Gerald Fischbach and Dr. Steven Hyman. Their idea was to create a center for neuroscience research that would house investigators from eight NIH institutes involved in neuroscience. The first phase of the building is due for completion in June 2004, with 100,000 square feet of research laboratory space. The second phase is scheduled to be ready in 2008. No patient activities will be performed in the Porter Building. Research will be conducted consistent with four themes: 1) Neurogenetics, 2) Channels, synapses, and small circuits, 3) Development and degeneration, and 4) Mood and cognition. Each I/C was asked to identify its best investigators in each theme area. There are other research themes represented within the Intramural programs, which will stay in Building 10, Building 49, and Twinbrook. The themes for the Porter Building will be flexible, in order to be responsive to the new NIH Director's priorities, the state of the science, and staff availability.

In response to a question about major administrative accomplishments, Dr. Landis cited the development of a new mechanism for resource allocation among investigators. Investigators have a significant amount of control of their budgets. A new mechanism for competitive funds was established to provide a way for investigators to increase their budgets. Other accomplishments are the completion of staff recruitment, the reorganization of the support system for clinical research, and plans to expand research space in the Porter Building and at two off-campus sites.

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X. Scientific Presentation

"Local Modulation of Immune System Activity Targeted to Blood Vessels Can Prevent Stroke"

Dr. John Hallenbeck, Chief, Stroke Branch, NINDS, presented a lecture describing a novel translational research project directed at the prevention of stroke. On the basis of his preclinical studies that implicated inflammatory and immune mediators in the genesis of stroke, Dr. Hallenbeck has devised a new approach to target suppression of immune and inflammatory reactions to segments of blood vessels that are becoming activated and are threatening to form a blood clot or to induce bleeding. His group had shown that blood vessel segments in the brain undergo local fluctuation between a state of low probability to form a blood clot or to bleed, and a state in which the probability of forming a blood clot or bleeding is higher. The intensity and frequency of this focal cycling was markedly increased in animals that were genetically stroke-prone. In addition, his group had noted that several proinflammatory molecules called cytokines that signal from one cell to another (specifically TNF and interleukin-1) activate endothelial cells that line the blood vessels and this precedes a stroke. Such activation was observed to mainly occur in animals with risk factors for stroke such as hypertension or advanced age. In a preclinical model, pharmacological blockade of these cytokines prevented strokes triggered by a strong inflammatory stimulus. This sort of body-wide suppression of the immune system, however, over the long term carries a high probability of adverse side effects. A potential strategy to circumvent this problem was suggested by his group's studies in which a specific brain protein administered by mouth led to tolerization of T lymphocytes to that protein and a suppression of immune and inflammatory reactions that was restricted to the brain. This technique, a form of mucosal tolerization, protected brain in a preclinical model of stroke induced by occlusion of the middle cerebral artery. On the basis of these preclinical studies, Dr. Hallenbeck chose to induce mucosal tolerization to E-selectin to determine if it would prevent spontaneous stroke in hypertensive, genetically stroke-prone rats. E-selectin is an adhesion molecule that is expressed on the surface of endothelial cells and binds to white blood cells. It is only expressed when local endothelial cells are becoming activated, an activation that in turn raises the threat of local formation of a blood clot or hemorrhage in that blood vessel segment. The strategy was to target suppression of immune and inflammatory reactions to blood vessel segments that were becoming activated and were posing a threat of local clot formation or hemorrhage. His group conducted studies of E-selectin tolerization in stroke-prone rats for several years and found that this strategy was highly effective in preventing stroke. The number of strokes as well as their size was strikingly reduced and hemorrhages were virtually eliminated. On the basis of these results, Dr. Hallenbeck and his group are initiating a Phase 1 clinical trial of the safety and tolerability of E-selectin tolerization for the prevention of stroke under a CRADA.

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XI. Review of the Division of Intramural Research Board of Scientific Counselors' Reports

In closed session, Dr. Landis presented the findings and recommendations of the Board of Scientific Counselors based on their review of specific DIR laboratories/units during 2002. The Council discussed the reports of the Board and accepted them.

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XII. Council Review of Pending Applications

This portion of the meeting, involving specific grant review, was closed to the public. The Council gave special attention to applications from foreign institutions and other applications, which needed specific discussion.

Research Training and Career Development Programs

The Council reviewed a total of 104 research career development and institutional training grant applications; of this total, 69 applications had primary assignment to NINDS, and 57 of them (82.6 percent) were recommended for support in the amount of $10.8 million first-year direct costs. It is anticipated that, of the research career development and institutional training grant applications competing at this Council, NINDS will be able to pay first-year direct costs of approximately $3.7 million.

Research Grant Awards

The Council reviewed a total of 1,292 research grant applications; of this total, 814 applications had primary assignment to NINDS, and 543 of them (66.7 percent) were recommended for support in the amount of $158.0 million first-year direct costs. It is anticipated that, of the research grants competing at this Council, NINDS will be able to pay first-year direct costs of approximately $51.7 million.

Senator Jacob Javits Neuroscience Investigator Awards

The Senator Jacob Javits Neuroscience Investigator Awards are made to distinguished investigators who have a record of scientific excellence and productivity, who are actively pursuing an area of research of strategic importance, and who can be expected to continue to be highly productive for a seven-year period. Candidates are nominated and selected at each Council meeting. At this meeting, the Council recommended one investigator as a Javits awardee.

Small Business Innovation Research and Small Technology Transfer Award Programs

The Council reviewed a total of 174 Small Business Innovation Research (SBIR) and Small Technology Transfer Award (STTR) grant applications; of this total, 92 applications had primary assignment to NINDS and 60 of them (65.2 percent) were recommended for support in the amount of $9.1 million first-year direct costs. It is anticipated that, of the SBIR and STTR applications competing at this Council, NINDS will be able to pay first-year direct costs of approximately $4.5 million.

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XIII. Adjournment

The meeting was adjourned at 10:20 a.m. on Friday, February 7, 2003.

We certify that, to the best of our knowledge, the foregoing minutes and attachments are accurate and complete.

_______________________________
 Constance W. Atwell, Ph.D.
Executive Secretary
National Advisory Neurological Disorders
and Stroke Council
Associate Director for Extramural Research
National Institute of Neurological Disorders and Stroke

_______________________________
 Audrey S. Penn, M.D.
Acting Chairperson
National Advisory Neurological Disorders
and Stroke Council
Acting Director
National Institute of Neurological Disorders and Stroke

These minutes will be formally considered by the Council at its next meeting. Corrections or notations will be incorporated in the minutes of that meeting.

A complete, printed copy of the Council minutes, including attachments, may be obtained by contacting:

Mrs. Ruth Linn
Committee Management Specialist
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Suite 3309
6001 Executive Boulevard, MSC 9531
Rockville, MD 20852-9531
(301) 496-9248
(301) 402-4370 (FAX)
linnr@ninds.nih.gov

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Last updated February 09, 2005