Molecular mechanisms of ARF family GTPases

ARF家族GTP酶的分子机制

• 批准号: 10330783
• 负责人: Richard A Kahn
• 金额: $ 57.21万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330783
• 关键词: Arl proteins; Biochemical; Biological; Cell Line; Cell physiology; Cells; Cellular biology; Centrosome; Cilia; Collection; Cytoskeleton; Energy Metabolism; Enzymatic Biochemistry; Family; Functional disorder; Genetic; Guanosine Triphosphate Phosphohydrolases; Heart Diseases; Human; In Vitro; Intervention; Knock-out; Link; Malignant Neoplasms; Membrane Protein Traffic; Molecular; Nerve Degeneration; Pathway interactions; Phylogenetic Analysis; Protein Biochemistry; Regulation; Retinal Degeneration; Signal Transduction; Signaling Protein; System; ciliopathy; cilium biogenesis; deafness; genome editing; human disease; insight; member; novel

Project Summary/Abstract Members of the ARF family of regulatory GTPases function as nodes in cell signaling to coordinate essential cell processes; including membrane traffic, energy metabolism, ciliogenesis, and the cytoskeleton. I have studied first ARF and later ARF-like (ARL) proteins for over 30 years, using a combination of biochemical, cell and molecular biological, genetic, and phylogenetic approaches and propose to continue these studies with a focus on their actions linked to cilia and centrosomes to allow more detailed mechanistic studies of a subset of five of the 30 GTPases in this family. We will use genome editing to generate a collection of knockout cell lines to decipher signaling by the proteins under study. And we will use classical protein biochemistry to purify and discover novel components in these pathways. We will both study functions of each of these five GTPases in cells, and link to in vitro biochemical studies of their enzymology. We will explore the potential for cross-talk or higher level ordering of cell signaling, and also develop novel, single actions for atypical GTPases as a means of determining shared or unique mechanisms within the family. A better understanding of these systems will reveal novel insights into fundamental aspects of cell biology as well as providing potential targets for intervention to alter the course of human diseases; including but not limited to cancer, heart disease, neurodegeneration, ciliopathies, retinal degeneration, and deafness.

项目总结/文摘