Intellectual Merit of Project: Trafficking of regulatory proteins into the cell nucleus, where genetic information is stored and processed, is fundamental to the organization and functioning of all living cells. Not surprisingly, this cellular traffic control is highly regulated and is directed by special signals called nuclear localization signals (NLS's), found within proteins destined for the nucleus. The NLS's directly interact with special transport proteins called importins that help guide the cargo into the nucleus. This project explores the signals regulating traffic control of thyroid hormone receptors, essential proteins which either activate or silence the expression of target genes in response to thyroid hormone, and play a pivotal role in development and metabolism. Specifically, the project will determine: 1) which importin serves as the primary carrier for the two NLS's in the thyroid hormone receptor; 2) the role that multiple NLS's play in regulating thyroid hormone receptor distribution and functional diversification, and 3) whether protein turn-over and routing to the proteasome, a special cellular component that acts like a garbage disposal system, play a role in thyroid hormone receptor trafficking. The thyroid hormone receptor provides an excellent model system for studying the role of multiple import and export signals in mediating traffic control of key regulatory proteins in the cell. This research will enhance general understanding of NLS structure and function, refine predictive tools, and provide insight into how a dynamic balance between nuclear import, retention, and degradation of regulatory proteins modulates the expression of essential genes.

Broader impacts of Project: A fruitful collaboration with faculty and undergraduates at Hampton University, an HBCU, will be continued. Opportunity for a diversity of undergraduates to gain hands-on experience with the scientific process will be provided. In the wider context, new techniques will be introduced to the departmental confocal microscope user group, and research activities will be integrated into an undergraduate lab course taught each Fall. Master's students will have the opportunity to gain experience in lab management and to develop their teaching skills through training and supervising undergraduates in the lab. This project will contribute substantially to human resource development in science, by preparing undergraduates and graduate students to go on to other graduate programs, medical school, veterinary school, secondary education, and industry, to name a few. In particular, this project will enhance the professional development of participants from groups underrepresented in science.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Gregory W. Warr
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College of William and Mary
United States
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