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 体内平衡 我实验室的首要目标是了解细胞如何产生和维持过氧化物酶体， 普遍存在的膜结合细胞器，具有特殊的代谢反应。 过氧化物酶体具有多功能性和动态性：细胞利用它们来适应环境，并且 因此可以通过改变酶含量、形态和结构来快速重塑其过氧化物酶体。 通过过氧化物酶体特异性自噬和从头生物发生产生的数量约为 35 Pex。 已知蛋白质有助于过氧化物酶体的形成和维持，但 此外，我们很可能无法在分子水平上解决它们的作用机制。 缺少许多重要的参与者，特别是在人类细胞中，并且缺乏基本的机械 知识阻碍了我们对过氧化物酶体如何促进人类健康的理解，无论是在 罕见的遗传性过氧化物酶体生物发生障碍 (PBD)，以及衰老过程中的疾病。 方法是利用蛋白质生物化学和酵母细胞生物学技术来剖析 Pex 蛋白的机制，特别关注 AAA-ATPase Pex1/Pex6。 识别 Pex1/Pex6 内源性底物的完整库和特征 对于底物选择很重要，因为 Pex1/Pex6 的突变导致大多数 PBDs，我们 进一步专注于使用致病等位基因来了解 Pex1/Pex6 的功能 人类细胞以及这些等位基因诱导的过氧化物酶体应激的细胞后果。 最后，我们发现了人类细胞中过氧化物酶体稳态的新型调节因子，并且正在研究中。 现在正在探索过氧化物酶体功能如何与所涉及的规范信号传导相整合 我们预计这项研究将增进我们对过氧化物酶体如何发挥作用的理解。 对人类健康和疾病做出贡献。