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The Regulation and Cellular Activities of the ARL2 GTPase

ARL2 GTPase 的调节和细胞活性

基本信息

批准号：
8964313
负责人：
Richard A Kahn
金额：
$ 32.84万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964313
关键词：
Address Affect Binding Biological Biology Cell division Cell physiology Cells Cellular biology Centrosome Complex Crista ampullaris Cytoskeleton Cytosol Disease Dissection Embryo Energy Metabolism Equilibrium Essential Genes Eukaryota Eukaryotic Cell Family Fibroblasts Functional disorder Funding Generations Grant Guanine Nucleotide Dissociation Inhibitors Guanosine Triphosphate Phosphohydrolases Hamman-Rich syndrome Health Heart Diseases Human Pathology Intervention Knockout Mice Link Malignant Neoplasms Mediating Membrane Membrane Protein Traffic Microtubules Mitochondria Modeling Molecular Molecular Chaperones Molecular Models Morphology Mus Nerve Degeneration Pathway interactions Phenocopy Point Mutation Preparation Process Production Proteins Reagent Regulation Retinal Degeneration Role Series Signal Transduction Site Small Interfering RNA System Testing Tubulin Work base cell growth regulation cell motility cofactor deafness density dimer human disease insight member molecular modeling mutant novel polymerization protein complex public health relevance

项目摘要

DESCRIPTION (provided by applicant): Members of the ARF family of regulatory GTPases function as nodes in cell signaling to coordinate essential cell processes; including membrane traffic, energy metabolism, and the cytoskeleton. The focus of this application is one of those GTPases, ARL2, and its binding partners. An understanding of the molecular mechanisms of ARL2 action to carry out or regulate essential cell processes will reveal novel insights into fundamental aspects of cell biology as well as providing potential targets for intervention to alte the course of human diseases; including but not limited to cancer, heart disease, neurodegeneration, retinal degeneration, and deafness. During the previous four years of funding we have provided rigorous tests of several models for ARL2 actions in different parts of eukaryotic cells, discarding some and refining others. We have also generated many key reagents, including the first purified protein preparations of mg levels of four different proteins and a series of point mutations in ARL2 that allow dissection of its different essential roles in eukaryotic cells. Thus, we are poised to make much more rapid progress in our understanding of the molecular mechanisms of regulation of tubulin folding and polymerization, ATP generation in mitochondria, and mitochondrial fission and motility. In the next funding period we propose three new, specific aims that are logical extensions of our previous work but which promise to have a far broader impact on several fields of cell signaling and regulation. In aim 1 we will test the model that ARL2 acts with the tubulin-specific co-chaperone cofactor D (TBCD) to regulate tubulin folding, microtubule density or polymerization, and less directly cell division. In aim 2 w will test the hypothesis that ARL2 regulates ATP production in mitochondria via changes in cristae remodeling and mitochondrial fusion. And in aim 3 we examine how mitochondrial fusion and motility are regulated by the ARL2 effector and GAP, ELMOD2.