CAREER: Circadian Control of Cell Division and Homeostasis

Virginia Polytechnic Institute And State University, Blacksburg VA

Investigators

Abstract

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). Intellectual Merit Circadian rhythms are mechanisms that measure time on a scale of about 24 h and adjust physiological processes to external environmental signals. Core circadian clock genes are defined as genes whose protein products are necessary components for the generation and regulation of circadian rhythms. Increasing evidence points to functional links between these proteins and cell division. Like the cell cycle network, circadian oscillation relies on autoregulatory loops generated by sequential phases of transcription/translation, protein modification, and degradation. Several studies have shown that approximately 7% of all known circadian controlled genes regulate either cell division or apoptosis. Although efforts have been made to identify circadian-controlled genes regulating cell-cycle progression and cell death, little is known about the metabolic signals modulating circadian regulation of gene expression. The primary goal of this project is to address the fundamental problem of how circadian factors sense metabolic changes and, consequently, act in cell-fate decisions. Here, a multi-technique approach, spanning from the atomic to the cellular level, will be used to elucidate the structural-functional properties of circadian transcription factors. The objectives are to i) define crosstalk mechanisms among cell cycle, circadian and metabolic components that influence cell cycle transitions ii) study the significance of metabolic signals for circadian rhythmicity and in cell death processes, and iii) determine the structural basis for sensing metabolic changes by circadian proteins. This project will help advance various areas of research by providing a mechanistic explanation for physiological changes accompanying cell division and by elucidating more fully the interplay among cellular mechanisms. Broader Impacts As the world economic base shifts increasingly towards technology, student participation and achievement in science is becoming increasingly important. Students need to understand that early involvement in science can open gates into all domains of academia and employment. In turn, professors must provide quality education to prepare their students to live and work in a world transformed by technological growth, international competitiveness, economic globalization, and increasing demographic shifts. This research initiative focuses on recruiting and training high school students and college undergraduates through research internships, which will provide them one-on-one, intensive experiences. These laboratory internships will permit students to develop an understanding of science concepts and skills and will produce deeper, more personal relationships with practicing scientists who can serve as role models and mentors. Through this project, efforts will focus on recruiting K-12 students from rural and urban areas in southwest Virginia while fostering undergraduate education. A second, and equally ambitious, goal of this initiative is to help resolve the scientific needs and technological challenges of our society and those in developing countries, specifically in Latin America. Here, the program focuses on two areas: secondary school education and graduate level training. The proposed research initiative includes components for training high school and graduate students from both Virginia and Latin America in advanced technologies in molecular biology while fostering social interactions and promoting collaborations with international institutions.