Department of Health and Human Services March 22, 2005 – Federal Register Recent Federal Regulation Documents

Macrophage cholesterol accumulation in blood vessels leads to the development of atherosclerotic plaques, the cause of most heart attacks and strokes. Recently, research from Dr. Howard Kruth, head of the Experimental Atherosclerosis Section of NHLBI has elucidated a novel mechanism of receptor-independent macrophage cholesterol accumulation\1,2\. In this pathway, human macrophages take up low- density lipoprotein (LDL), the main carrier of blood cholesterol, by fluid-phase endocytosis, an uptake pathway that can be activated in macrophages. Activated macrophages show greatly stimulated uptake of fluid and LDL contained in the fluid through macropinocytosis, a fluid- phase endocytic uptake pathway unique to macrophages. This mechanism of LDL uptake and macrophage cholesterol accumulation does not depend on binding of LDL to receptors. Macrophage macropinocytosis of LDL produces levels of cholesterol accumulation similar to that observed for macrophages isolated from atherosclerotic plaques, something that does not occur when human macrophages take up LDL by receptor-mediated mechanisms in these macrophages. The NHLBI is seeking CRADA collaborators to work with investigators in the Experimental Atherosclerosis Section of NHLBI to identify inhibitors of this cholesterol uptake pathway. The collaborator will provide high throughput screening capabilities coupled with small molecule and/or siRNA libraries of test compounds, or other methodologies to identify potential inhibitors of this pathway. A cell- based screening assay that will have predictive value with human macrophages will be developed jointly by the NHLBI investigators and the collaborator based on published and unpublished research findings of the NHLBI investigators. The goal of this collaboration will be to identify compounds that selectively inhibit macrophage macropinocytosis and consequently macrophage uptake of LDL and cholesterol accumulation. Compounds identified will be further tested in a suitable animal model of atherosclerosis to determine their effect on macrophage cholesterol accumulation and atherosclerotic plaque development. Macropinocytosis also mediates entry of microorganisms such as HIV into macrophages. Thus, discovery of macropinocytosis inhibitors may be relevant not only to atherosclerosis treatment but also to certain infectious disease treatments.

This announcement governs the proposed award of formula grants under the Family Violence Prevention and Services Act to States (including Territories and Insular Areas). The purpose of these grants is to assist States in establishing, maintaining, and expanding programs and projects to prevent family violence and to provide immediate shelter and related assistance for victims of family violence and their dependents. This announcement sets forth the application requirements, the application process, and other administrative and fiscal requirements for grants in fiscal year (FY) 2005. CFDA Number: 93.671, Family Violence Prevention and Services.

The Food and Drug Administration (FDA) is requesting nominations for nonvoting industry representatives to serve on the National Mammography Quality Assurance Advisory Committee (NMQAAC) in the Center for Devices and Radiological Health (CDRH). FDA has a special interest in ensuring that women, minority groups, individuals with disabilities, and small businesses are adequately represented on its advisory committees. Therefore, the agency encourages nominations for appropriately qualified candidates from these groups.