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Your Environment. Your Health.

EXPLORING THE ROLE OF MITOCHONDRIAL HOMEOSTATIC PROCESSES IN THE ACCUMULATION AND TRANSMISSION OF ENVIRONMENTALLY-INDUCED MTDNA MUTATIONS ACROSS GENERATIONS

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Principal Investigator: Leuthner, Tess Catherine
Institute Receiving Award Duke University
Location Durham, NC
Grant Number F31ES030588
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Feb 2020 to 31 Jan 2022
DESCRIPTION (provided by applicant): Abstract    Mitochondrial dysfunction results in disorders that affect one in 4,000 people, and diseases associated  with aging, such as neurodegeneration and cancer. Improper function of a mitochondrial quality control  process, mitophagy, as well as mutations in mitochondrial DNA (mtDNA) are implicated in these  diseases. The role of environmental pollutants and mitophagy in the origin and transmission of mtDNA  mutations is poorly understood. The objective of this proposal is to investigate variation in susceptibility  to chemical-­induced mtDNA damage in the context of mitochondrial homeostatic processes, how DNA  damage can lead to mtDNA mutations, and the functional consequences of these mutations. The model  organism Caenorhabditis elegans has a highly conserved mitochondrial genome and well characterized  mitochondrial biology, and provides an extremely tractable genetic and toxicological model for this  research proposal. We hypothesize that C. elegans that are genetically deficient in mitophagy will  accumulate and retain higher levels of mtDNA damage compared to wild type after exposure to the  environmental toxicants and known mutagens, cadmium and Aflatoxin B1. We propose that this will  increase mtDNA mutation frequencies. This work will also inform the role of mitophagy in transmission  of mtDNA mutations into the next generation. To detect rare mtDNA mutations, we will adapt a well-­ established and highly-­sensitive sequencing platform, Duplex Sequencing, for C. elegans for the first  time. This will fulfill a significant goal of the training plan, which is to become proficient in computational  biology and bioinformatics. We will also investigate the potential health effects on the organism,  including mitochondrial function, reproduction, and lifespan as a consequence of mtDNA mutations.  Overall, this research is impactful because it will provide better understanding of the role that exposures  to environmental pollutants and genetic susceptibility play in the origin, signature, transmission, and  effects of mtDNA mutations.        
Science Code(s)/Area of Science(s) Primary: 64 - Mitochondrial Disorders
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Daniel Shaughnessy
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