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A Systems Approach to Discover Sensors and Regulators of the Mitochondrial Genome

发现线粒体基因组传感器和调节器的系统方法

基本信息

批准号：
10589232
负责人：
Sneha Prakash Rath
金额：
$ 12.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589232
关键词：
Address Age Alzheimer&apos s Disease Autoimmune Diseases Autoimmune Responses Autophagocytosis Award Awareness Bioenergetics Biological Biology Biosensor Blood CRISPR screen Categories Cell model Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Computer Analysis Core Protein Custom Cytosol Data Dedications Disease Doctor of Philosophy Drug Targeting Electron Transport Energy Metabolism Equilibrium Eukaryota Evolution Extravasation Faculty Future Genes Genetic Genetic Screening Genetic study Genome Goals Growth Homeostasis Human Immune Immunologic Surveillance Immunologist Immunology Impairment Inflammatory Institution Instruction Interferons Knock-out Laboratories Link Membrane Potentials Mentors Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Matrix Molecular Molecular Machines NADH Natural Immunity Nuclear Nucleotides Ovum Oxidation-Reduction PINK1 gene Parkinson Disease Pathology Pathway interactions Phase Postdoctoral Fellow Proline Prosthesis Protein Import Proteins Publishing Regulation Reporter Research Research Personnel Respiratory Chain Role Signal Transduction Stimulator of Interferon Genes Stress Syndrome System Systems Biology Testing Therapeutic Tissues Training Trypanosoma United States National Institutes of Health Work Yeasts Yin age related biological adaptation to stress career cell growth clinically relevant density design ds-DNA endosymbiont experience experimental study fitness follow-up genome-wide immune function immunogenic improved interest member mitochondrial dysfunction mitochondrial genome mitochondrial membrane multiple omics novel post-doctoral training programs response screening sensor small molecule inhibitor theories therapeutic candidate time use

项目摘要

Abstract Over their ~1.5-billion-year evolution from a bacterial endosymbiont, mitochondria have retained genes essential for energy metabolism on their own distinct genome (mtDNA) in almost all eukaryotes. Human mtDNA encodes 13 core proteins in the respiratory chain and varies up to 10,000-fold in copy number from ~100 in blood to ~half a million in the unfertilized egg, with each cell maintaining an intrinsic, optimal setpoint via yet unknown mechanisms. A decline in this setpoint causes rare but severe disorders with no proven therapies and underlies the common age-related mitochondrial dysfunction with relevance to Parkinson’s and Alzheimer’s Disease. In my K99 phase, I propose to address two major unmet needs in clinical and basic mitochondrial biology – to overcome the detrimental consequences of mtDNA loss and to understand homeostatic regulation of mtDNA copy number. Genetic studies in yeast, trypanosomes, and my published work in human cells, reveal a conserved link between membrane potential and tolerance to mtDNA loss. In aim 1, I will determine the mechanism by which boosting membrane potential rescues the growth of mtDNA-depleted cells. My completed multi-omic profiling of mtDNA depletion and repletion states has identified a small number of candidate effectors of membrane potential which I will test using a drug that targets stress signaling, a metabolite that can be supplemented exogenously, and a protein prosthetic for redox manipulation pioneered by my mentor’s lab. In aim 2, I will take a more unbiased approach and systematically identify nuclear regulators of human mtDNA copy number for the first time using a FACS-based genome-wide CRISPR knockout screen, which I conceptualized and developed in my early postdoctoral work. While my K99 focuses on mtDNA sensing and regulation within the mitochondrial matrix, my R00 (aim 3) examines the pathways and immunogenic consequences of mtDNA leakage to the cytosol which is highly relevant to autoimmune disorders. Thus, my independent research program aims at a synergistic culmination of postdoctoral training in mitochondrial systems biology and PhD expertise in innate immunity. Through my K99 goals I will master the theory and experimentation of bioenergetics and get hands-on training in high-throughput genetics, from screen design to computational analysis. My mentor, Dr. Vamsi Mootha, is a world leader with >20 years of experience in precisely the field of my proposed training – mitochondrial systems biology – and has propelled over a dozen trainees into thriving academic research careers. I have a diverse advising committee with local and national experts relevant to my proposal, including one junior faculty member in my department and one immunologist for specific guidance at the R00 transition. Thus, with the NIH Pathway to Independence award, I will train towards my long-term goal of launching my own laboratory and discovering basic molecular mechanisms underlying mitochondrial and autoimmune diseases.

摘要