Endocytic Trafficking in C. elegans and Mammals

线虫和哺乳动物的内吞贩运

• 批准号: 7228519
• 负责人: Barth Demian Grant
• 金额: $ 26.16万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228519
• 关键词: Applied Research; Binding; Biochemical; Biological; Biological Models; Biological Process; Biology; Caenorhabditis elegans; Cell surface; Cells; Cellular biology; Collaborations; Complement; Complex; Defect; Depth; Endosomes; Fluorescence Recovery After Photobleaching; Fractionation; Genes; Genetic; Grant; Homologous Gene; Human; Huntington Disease; Hydrolysis; Mammalian Cell; Mammals; Mediating; Mediator of activation protein; Membrane; Membrane Protein Traffic; Membrane Proteins; Membrane Transport Proteins; Microbe; Modeling; Molecular; Molecular Genetics; Morphology; Mutation; Myeloid Leukemia; Nematoda; Nucleotides; Participant; Pathway interactions; Pattern; Peripheral; Phage Display; Process; Property; Proteins; RNA Interference; Reaction; Recycling; Structure; System; Techniques; Testing; Therapeutic; Thinking; Time; Transmembrane Transport; Transport Process; Work; Yeasts; endosome membrane; hypercholesterolemia; in vivo; interest; mutant; novel; novel strategies; tool; trafficking; yeast two hybrid system

DESCRIPTION (provided by applicant): Regulated membrane and protein transport is a central component of a multitude of biological processes and is critically important in human heath. For example, transport defects are implicated in hypercholesterolemia, Huntington's disease, and myeloid leukemia. Thus, elaborating molecular mechanisms of membrane trafficking are profoundly important to both basic and applied research. Our interests are in exploiting advantageous features of C. elegans and mammalian cells to investigate one of the least understood steps in endocytic traffic-the return of internalized molecules to the cell surface via recycling endosomes. Surprisingly little is known of the molecules that mediate and regulate this step of recycling. Initial studies indicate this process is highly conserved in metazoans, and may be distinct from related processes in microbes like yeast. Using a genetic approach in C. elegans, we have identified novel proteins that are critical for the recycling process in vivo. One of these, RME-1, is a peripheral membrane protein of the recycling endosome that regulates export from the recycling endosome in a process thought to utilize membrane tubules. RME-1 appears highly conserved between nematodes and mammals in both structure and basic function and is one of the first proteins clearly implicated in this specific recycling step. Mutations in a second protein, GUM-l, cause the same biological defects as mutations in RME-I. Furthermore, GUM-1 is required for the localization of RME-1 to endosomes. The molecular identity of the GUM-1 protein and the mechanism by which it regulates RME-1 localization are currently unknown. We plan to decipher the biology of endocytic recycling by conducting an in-depth multi-pronged analysis of RME-1 and GUM-1 and by applying novel approaches toward the identification of additional proteins that act with RME-1 and GUM-1 in the process of recycling. Our specific aims are: l) To test key working hypotheses that RME-1 is regulated by nucleotide binding and membrane association, and that RME-1 participates in membrane tubule formation. 2) To characterize GUM-l, a novel regulator of endocytic recycling in C. elegans and mammals. 3) To identify additional mediators and regulators of endocytic recycling in C. elegans. By combining the power of C. elegans genetics and mamalian cell biology this work will significantly advance our understanding of .the mechanisms determining a key metazoan membrane transport process.

描述（由申请人提供）：受调节的膜和蛋白质运输是众多生物过程的核心组成部分，对人类健康至关重要。例如，运输缺陷与高胆固醇血症、亨廷顿氏病和髓性白血病有关。因此，阐明膜转运的分子机制对基础研究和应用研究都具有深远的意义。