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-项目总结：研究过氧化物酶体的机制 内稳态 我的实验室的首要目标是了解细胞是如何制造和维持过氧化物体的 无处不在的膜结合细胞器，具有特殊的代谢反应。 过氧化物体既是多功能的，也是动态的：细胞利用它们来适应环境，并且 因此可以通过改变酶的含量、形态和结构来快速重塑它们的过氧化物体 通过过氧化物酶体特异的自噬和从头生物发生的数量。约35像素 已知蛋白质有助于过氧化酶体的形成和维持，但 它们的作用机制不是在分子水平上解决的。此外，我们很可能 缺少许多重要的角色，特别是在人类细胞中，以及这种基本机制的缺乏 知识阻碍了我们理解过氧化物酶如何有助于人类健康，无论是在 罕见的遗传性过氧化物体生物发生障碍(PBD)，以及在衰老过程中。我们的 方法是使用蛋白质生物化学和酵母细胞生物学的技术来剖析 Pex蛋白的作用机制，尤其是AAA-ATPase Pex1/Pex6。我们的目标是 确定Pex1/Pex6‘S内源底物的完整谱系及其特征 对于底物的选择很重要。由于Pex1/Pex6的突变导致了大多数的多发性骨髓疾病，我们 进一步侧重于利用致病等位基因来理解Pex1/Pex6在 人类细胞和由这些等位基因引起的过氧化物体应激的细胞后果。 最后，我们已经确定了人类细胞中过氧化物酶体内平衡的新调节器，并且是 现在正在探索过氧化体功能如何与所涉及的正则信号相结合 小路。我们预计这项研究将提高我们对过氧化物酶如何 有助于人类的健康和疾病。