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父母赠款 - 项目摘要：调查过氧组合的机制 稳态 我实验室的总体目标是了解细胞如何制造和维持过氧化物体，一个 无处不在的膜结合细胞器，该细胞器具有专门的代谢反应。 过氧化物体既多功能又动态：细胞使用它们适应其环境，并且 因此，可以通过改变酶含量，形态和 大约35 pex 众所周知，蛋白质会导致过氧化物组的形成和维持，但 它们作用的机制未在分子水平上解决。此外，我们很可能 缺少许多重要的参与者，尤其是在人类细胞中，而且缺乏基本机械 知识阻碍了我们对过氧化物组对人类健康的贡献的理解 罕见的，遗传过氧化物体生物发生障碍（PBD）和衰老过程中。我们的 方法是在蛋白质生物化学和酵母细胞生物学中使用技术来剖析 PEX蛋白的机理，尤其是针对AAA-ATPase PEX1/PEX6的机理。我们的目标 确定PEX1/PEX6的内源性底物的完整曲目以及 对于底物选择很重要。由于PEX1/PEX6中的突变会导致大多数PBD，因此我们 进一步专注于使用引起疾病的等位基因了解PEX1/PEX6在 这些等位基因诱导的过氧化物胁迫的人类细胞和细胞后果。 最后，我们已经确定了人类细胞中过氧化物体稳态的新型调节剂，并且是 现在探索过氧化物体功能如何与隐含的规范信号集成 途径。我们预计这项研究将提高我们对过氧化物体的理解 有助于人类健康和疾病。