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Freedom of Information Act Office

IC Directors' Meeting Highlights

April 15, 2009

To: IC Directors
Subject: IC Directors Meeting Highlights—March 12, 2009, Shannon Building, Wilson Hall

ARRA update: Dr. Lawrence Tabak (OD/NIDCR)

Dr. Tabak updated IC Directors on multiple activities associated with the NIH Implementation of the American Recovery and Reinvestment Act of 2009 (ARRA). Included in the discussion were plans for Challenge Grants, Grand Opportunities Grants and Signature projects. Institutes were encouraged to use all mechanisms at their disposal when identifying projects and the Office of the Director will consider co-funding a subset of Signature projects. Programs are also being considered to support career development and community-based research.

As a brief update, Dr. Story Landis informed the Directors that NIH is working to develop new guidelines regarding research using stem cells. A notice will be posted in the NIH Guide as soon as possible which will also contain some interim guidance.

Rare and Neglected Diseases Initiative (RNDI): Dr. Steve Groft (ORD), Dr. Chris Austin (NHGRI), Dr. Alan Guttmacher (NHGRI)

Dr. Groft highlighted the problem of rare and neglected diseases (RND), "rare" being defined as one of 6000 diseases with U.S. prevalence <200,000, and "neglected" as occurring chiefly among impoverished and marginalized populations in nations unable to afford treatments; both groups of diseases have a paucity of pharmacotherapy available because of low return on investment. In the summer of 2008, Dr. Elias Zerhouni received Congressional support for an NIH initiative to develop therapies for RND that was subsequently inserted in FY09 House and Senate budget report language. In anticipation that $24M will be appropriated for the RNDI in FY2009, a 5-year budget and a plan has been devised for the initiative. 

The Rare and Neglected Diseases Initiative (RNDI) will be governed by the Office of Rare Diseases Research (ORDR), and will build on the work and operational model of the NIH Chemical Genomics Center (NCGC), combining the operational strengths of intramural with the scientific diversity of extramural; the RNDI's science will start where the NCGC's leaves off. Dr. Chris Austin outlined how the chemical probes produced by the NCGC and the other Molecular Libraries centers are useful for basic research but are just the start of drug development; RNDI will perform the medicinal chemistry and preclinical ADME and toxicology that are required for an Investigational New Drug application; the RNDI will license out these compounds as soon as a biotechnology, pharmaceutical, or foundation entity would be willing to license them for clinical development. Approximately 20% of the RNDI's effort will go to technology and paradigm development to improve the currently dismal success rate of developing IND compounds from chemical probes. At the start, 5 projects per year will be run by RNDI.

To govern the Initiative, the ORDR will organize 2 advisory groups – a Trans-NIH Staff Advisory Group to provide consultation regarding operation of the RNDI, and an Expert External Panel to assess progress of the Initiative, make recommendations and provide second-level review of applications for use of the RNDI facility. 

Discussion: IC Directors asked how the RNDI is to be funded for 5 years. John Bartrum, Associate Director for the Office of Budget, explained that Congress inserted funds for the program into every IC, and the RNDI will subsequently collect those funds through an IC tap. Several directors noted that $24M will not be sufficient for this effort and that care will need to be exerted when selecting projects from the wide range of diseases which could be studied.

The Biophysics of Exocytosis and Endocytosis: Dr. Joshua Zimmerberg (NICHD), with introduction by Dr. Duane Alexander (NICHD)

Dr. Alexander introduced Dr. Zimmerberg as a highly regarded scientist who has had a successful and long-standing association at the NIH as a research fellow and a scientist at several NIH ICs. He currently is in charge of 2 significant efforts, one is a collaboration with NASA involving 3-dimensional cell arrays and the other is an study on the biophysics of membrane fusion, which is the subject of today’s presentation.

Dr. Zimmerberg explained that our current understanding of vesicle fusion and exocytosis, while applicable to many processes in human physiology, provides a limiting snapshot of the events taking place. There is a gap of knowledge in our understanding of the cellular environment and the events that take place in order to overcome the energy barriers for catalyzing exocytosis or endocytosis. Studies on pore conductance of mast cells revealed that these lipid nanotubes stabilized. Therefore, membrane fission became the focus of subsequent efforts. Dynamin was targeted as playing a role in membrane fission and subsequent experiments demonstrated that dynamin squeezes nanotubes in a lipid-dependent manner. Narrowing of the tube is necessary for tube fission with GTP hydrolysis allowing for relaxation of the curvature and lipid rearrangement.

Critical concepts and perspectives in reaching these conclusions are that proteins cooperate with lipids and act in a distance, proteins provide ring-like boundary conditions for topological transformation that is driven by lipid energetics, and localized high curvature stress can be relieved through cooperative lipid tilting and hemi-fission. More ultra-structural data and quantitative lipid dependence data are needed, and protein-lipid interactions need to be better understood.

This page last reviewed on September 28, 2011

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