Molecular Mechanisms of FUNDC1-Mediated Mitophagy

FUNDC1介导的线粒体自噬的分子机制

• 批准号: 10461452
• 负责人: Jose M Delgado
• 金额: $ 4.68万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461452
• 关键词: Adenoviruses; Autophagocytosis; BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like; BNIP3L gene; Bypass; CRISPR screen; CRISPR/Cas technology; Cardiovascular Diseases; Cells; Communication; Data; Development; Disease; Ensure; Event; Experimental Designs; Fibrinogen; Future; Genes; Genetic; Genetic Screening; Goals; Homeostasis; Human Pathology; Hypoxia; Laboratories; Lipids; Lysosomes; Malignant Neoplasms; Mediating; Membrane; Mentorship; Mitochondria; Molecular; Monitor; Mutate; Organelles; Outcomes Research; Outer Mitochondrial Membrane; Oxygen; Oxygen Consumption; PINK1 gene; Parkin; Pathology; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Proteins; Receptor Activation; Regulation; Reperfusion Injury; Reporter; Research; Research Personnel; Research Project Grants; Role; Science; Site; Stress; Technical Expertise; Therapeutic; Training; base; career; college; experience; experimental study; genome-wide; high throughput technology; insight; interest; mutant; novel; programs; receptor; response; skills; success; therapeutic target; tool; ubiquitin-protein ligase

ABSTRACT Autophagy is a lysosome-mediated pathway that selectively targets and degrades cytoplasmic content. Identification of autophagy targets is a critical facet of cellular homeostasis and is mediated by selective autophagy receptors. Immense progress has been made in characterizing soluble autophagy receptors. However, mechanisms of recently discovered membrane-embedded receptor Fun14 domain-containing 1 (FUNDC1) remains widely unknown. Located on the outer mitochondrial membrane, FUNDC1 mediates autophagic turnover of mitochondria, termed mitophagy. FUNDC1-mediated mitophagy is induced in diverse pathologies and developmental programs. For example, previous studies have demonstrated a physiological role for FUNDC1-mediated mitophagy in hypoxia-related pathologies, including cancer and ischemia-reperfusion injury. Preliminary results suggest that FUNDC1-mediated mitophagy is molecularly distinct from other forms of mitophagy. The overall objective of this proposal is to elucidate the molecular mechanisms of hypoxia-induced selective autophagy pathways through the characterization of FUNDC1 function. In Aim 1, a domain analysis approach will be performed to identify functionally important regions of FUNDC1 required for hypoxia-induced mitophagy. These studies will dissect potential activation events that enable activation of FUNDC1. In Aim 2, CRISPR-Cas9 technology for high-throughput genetic screens will be used to identify modulators of FUNDC1 turnover. Novel genetic factors that modulate FUNDC1-mediated mitophagy will be characterized for their function. Taken together, the proposed experiments will provide insight to elucidate mechanisms of hypoxia- induced selective autophagy and expand putative therapeutic targets for autophagy in hypoxic-related human pathologies. With the proposed training plan, I will enhance the skills needed to progress my scientific research career including laboratory technical skills, experimental design, science communication, and mentorship. Dartmouth College and my mentorship team are well-equipped to ensure success of my research project and progression to the next step of my academic career as a postdoctoral researcher.

摘要