Novel function of chloride intracellular channel protein (CLIC) and TGF-beta signaling in stress response and healthspan in Caenorhabditis elegans

Borough Of Manhattan Community College, New York NY

Investigators

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Abstract

? DESCRIPTION (provided by applicant): The global population age 65 and over has been growing significantly, which poses public health and economic issues to the United States. It is critical for us to understand the nature of aging and define the mechanisms that extend healthspan - the length of time an individual is able to maintain good health. Stress affects aging significantly. Dissecting the molecular mechanisms of stress pathways should help us to manage healthy aging. This work focuses on an understudied stress-responsive gene: chloride intracellular channel protein (Clic) and TGF-beta signaling in a simple organism C. elegans. Research from cell culture showed that mammalian Clic4 is a multifunctional gene that regulates cellular stress and modifies TGF-beta signaling. However, mutants defective in the C. elegans Clic homolog exl-1 had no observable phenotype until our recent research studies. We demonstrated that exl-1 loss-of-function mutants are more susceptible to heat stress than wild type animals. EXL-1 protein translocates from the cytoplasm into the nucleus under thermal stress. Furthermore, the mutants also demonstrated sarcopenia phenotype at an earlier adulthood than wild type animals. Adapting to temperature change is a fundamental requirement for animal survival and development, as well as cellular homeostasis. Thus, this work has a high scientific significance in investigating genes regulating environmental stress, in particular heat. We hypothesize that: exl-1/Clic functions in the DBL-1/TGF-beta pathway to modulate thermal stress and healthspan. To test our hypothesis, we will determine: 1. the effects of DBL-1/TGF-beta pathway components on EXL-1 nuclear translocation and animal survival under thermal stress; 2. role of exl-1 in animal healthspan. Upon completion of the project we will uncover genetic and molecular mechanisms of Clic and TGF-beta regulated stress response and healthspan. The work will provide the first link of exl-1/Clic and DBL-1/TGF-beta signaling with thermal stress and give us valuable insights of exl-1/Clic physiological function in intact animals This project will also bring in active research to a two-year college, and engage undergraduate students in a minority-serving institution, an important educational significance of this work.