Research Supplements for Underrepresented Minorities

PART 2, DESCRIPTION OF THE RESEARCH PLAN Abstract of 5ROIAI050656 Natural killer (NK) cells use killer immunoglobulin-like receptors (KIR) to distinguish normal cells from infected and malignant cells. NK cells express an apparently random assortment of KIR genes. Our LONG-RANGE GOAL is to use NK cells to treat cancer and infectious diseases. Our CURRENT OBJECTIVE is to identify how developing NK cells initiate and then maintain selective KIR gene expression. Supported by strong preliminary data, our CENTRAL HYPOTHESIS is that promoter methylation controls locus-specific and allele-specific KIR gene expression. The RATIONALE for the proposed research is that understanding KIR gene regulation could lead to effective immunotherapy of cancer and infectious diseases. Furthermore, our research will test the central paradigm of tissue-specific gene expression. Our SPECIFIC AIMS are to 1. Test the molecular mechanisms ofKIR gene expression control. 2. Define cis-acting elements and trans-acting factors that control KIR gene expression. 3. Elucidate how developing NK cells initiate selective KIR gene expression. Our approach is INNOV ATlVE. We have produced unique new data and we will combine several cutting-edge research techniques to rigorously test our hypotheses. It is our EXPECTATION that I) we will develop a clear understanding of how NK cells maintain stable KIR expression; 2) we will define several important cis-acting elements and trans-acting factors that regulate KIR transcription; 3) we will identify what signals developing NK cells to initiate KIR gene expression. Our results will be highly SIGNFICANT, because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Of broader significance, elucidation of KIR gene expression control will provide an important model for gene choice in development and offer insights into birth defects and cancer. Overview of Career Development Plan Dr. Ramilo-Narkevic is at a stage of her career in which she almost ready for a faculty position. I believe that the right kind of training will help her mature into a faculty member who competes successfully for independent grant support and who teaches, beginning in the Fall Semester, 2007. The 3.5 year Career Development Plan is designed to give Dr. Ramilo-Narkevic outstanding credentials in both research and teaching. In the past Dr. Ramilo-Narkevic has applied her considerable skills in protein biochemistry to topics in enzymology and DNA repair. The Research Plan will broaden her research experience by investigation of molecular control of gene expression. The combination of sophisticated protein biochemistry and molecular biology will give her an excellent set of techniques and research approaches. In her future work as an independent investigator, Dr. Ramilo-Narkevic will use these skills to elucidate how trans-acting factors interact to control KIR gene expression in human health and disease. Lymphocyte transcription control, epigenetic control, and immunotherapy are now receiving considerable attention and likely will form the basis for her first grant application. At the same time that she investigates gene transcription, Dr. Ramilo-Narkevic will strengthen her teaching experience through a unique program at the University of Kentucky. The Teaching Plan is to enroll Dr. Ramilo-Narkevic in didactic classes and a college teaching practicum leading to a Graduate Certificate in College Teaching and Learning. The courses are structured so that the teaching experience does not interfere with the Research Plan.