Investigating the mechanisms of peroxisome homeostasis

研究过氧化物酶体稳态机制

• 批准号: 10808484
• 负责人: Brooke Meghan Gardner
• 金额: $ 1.36万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10808484
• 关键词: ATP phosphohydrolase; ATPase Domain; Aging; Alleles; Aspartic Acid; Autophagocytosis; Binding; Biogenesis; Biological Assay; Blindness; Bone Diseases; Cells; Cellular biology; Data; Disease; Environment; Enzymes; Fluorescence; Future; Genetic; Glycine; Goals; Health; Homeostasis; Human; Human Cell Line; Hydrophobicity; Kidney Diseases; Knowledge; Liver diseases; Maintenance; Membrane; Metabolic; Molecular; Morphology; Mutation; Nerve Degeneration; Nucleotides; Oranges; Organelles; PHEX protein; Process; Protein Biochemistry; Reaction; Research; Signal Pathway; Stress; System; Techniques; Ubiquitin; Yeasts; Zellweger Syndrome; disease-causing mutation; experience; hearing impairment; improved; multicatalytic endopeptidase complex; mutant; novel; overexpression; parent grant; peroxisome; peroxisome membrane; small molecule; summer research

R35 Parent Grant – Project Summary: Investigating the mechanisms of peroxisome homeostasis The overarching goal of my lab is to understand how cells make and maintain peroxisomes, a ubiquitous membrane-bound organelle that harbors specialized metabolic reactions. Peroxisomes are both versatile and dynamic: cells use them to adapt to their environment, and thus can rapidly remodel their peroxisomes by altering enzyme content, morphology, and number through peroxisome-specific autophagy and de novo biogenesis. Approximately 35 Pex proteins are known to contribute to peroxisome formation and maintenance, yet the mechanisms by which they act are not resolved at a molecular level. Furthermore, we are likely missing many important players, especially in human cells, and this lack of basic mechanistic knowledge hinders our understanding of how peroxisome contribute to human health, both in rare, genetic Peroxisome Biogenesis Disorders (PBDs), and during the aging process. Our approach is to use techniques in protein biochemistry and yeast cell biology to dissect the mechanism of the Pex proteins, particularly focusing on the AAA-ATPase Pex1/Pex6. We aim to identify the full repertoire of Pex1/Pex6’s endogenous substrates and the features that are important for substrate selection. Since mutations in Pex1/Pex6 cause the majority of PBDs, we are further focused on using disease-causing alleles to understand Pex1/Pex6 function in the human cells and the cellular consequences of peroxisome stress induced by these alleles. Finally, we have identified novel regulators of peroxisome homeostasis in human cells, and are now exploring how peroxisome function integrates with the implicated canonical signaling pathways. We anticipate that this research will improve our understanding of how peroxisomes contribute to human health and disease.

R35家长资助-项目摘要：研究过氧化物酶体的机制