Understanding mitochondrial mutations that drive human tissue aging
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PROJECT SUMMARY/ABSTRACT This proposal describes a five-year mentored physician-scientist training program to define the scope and functional consequences of mitochondrial genome mutations in skin tissue aging. The mitochondrial genome (mtDNA) is an extranuclear source of genetic variability that regulates critical cell functions. MtDNA is highly susceptible to mutagenesis, including the development of large deletion mutations. When a mutation is present, it can affect all copies, or only a fraction of the copies of mtDNA. This portion is referred to as heteroplasmy. Increased levels of mtDNA mutation heteroplasmy have been frequently reported in aging tissue. Despite this potential, the scope and consequences of age-related mtDNA mutations are not well understood due to difficulties in sequencing mtDNA and a paucity of in vitro models, making it challenging to use these mutations as a metric of aging or to develop targeted interventions. To address these limitations, I developed a long-read sequencing method to profile mtDNA and an induced pluripotent cell-based system to study the impact of high mtDNA mutation heteroplasmy in multiple cell types. Aged facial skin contains the highest frequency of mtDNA deletion mutations across tissues profiled and prior work suggests a link between mtDNA and function of skin keratinocyte progenitor cells. Skin thus offers an appealing system to begin understanding the breadth and consequences of age-associated mtDNA mutations. I hypothesize that mtDNA alterations are acquired with aging in a tissue specific pattern and directly contribute to age-associated functional changes. To test this, I will pursue three study aims 1) Map and determine the tissue specificity of mtDNA mutations in aged skin, 2) Quantify mtDNA genetic diversity in age- associated neoplasia, and 3) Determine whether high mtDNA mutation heteroplasmy alters the function of human iPSC-derived keratinocyte progenitor cells. This work will provide foundational knowledge for the study of mitochondrial genome mutations in aging. The K08 will support me to develop advanced skills in the identification acquired genomic variation and the use of pluripotent and progenitor cells in the study of aging in order to become a pioneering physician scientist studying the biology of aging. Dr. Michael Teitell, a world- renowned expert in the study of mitochondrial metabolism and highly experienced and successful mentor, will serve as my primary mentor. Dr. Jonathan Wanagat and Dr. Paul Boutros will offer guidance in the study of mitochondrial genomic variation, Dr. Thomas Rando will offer guidance in the study of progenitor cell aging and Dr. Phillip Scumpia will guide work studying cutaneous tissue, all as members of my advisory committee. A K08 award will enable my carving out a unique, critical niche of multidisciplinary research that blends mitochondrial genomics and regenerative biology at the launch of my career as an independent investigator.
