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Gng5 function in neural progenitors

Gng5 在神经祖细胞中的功能

基本信息

批准号：
8360905
负责人：
JANET D ROBISHAW
金额：
$ 8.18万
依托单位：
GEISINGER CLINIC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8360905
关键词：
Ablation Address Adenylate Cyclase Adult Affect Alleles American Amino Acids Animals Biological Process Brain Bypass Cell physiology Characteristics Child Communities Community Developments Congenital Disorders Congenital Heart Defects Defect Degenerative Disorder Development Disease Embryo Event Exhibits Foundations Future G Protein Gene G-Protein-Coupled Receptors GTP-Binding Proteins Gene Family Gene Targeting Genes Goals Guanosine Triphosphate Health Heterotrimeric GTP-Binding Proteins Human Genome Individual Ion Channel Knock-out Knockout Mice Maintenance Microcephaly Molecular Molecular Profiling Mus National Institute of Child Health and Human Development National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neurons Neurosciences Organism Phospholipase Play Post-Translational Protein Processing Process Production Protein Subunits Proteins Regulation Research Resources Role Second Messenger Systems Signal Pathway Signal Transduction Transgenic Mice Translating aging population base design dimer improved insight migration mouse genome mouse model nerve stem cell nervous system disorder nestin protein neural precursor cell neurodevelopment neurogenesis neuron loss neurotrophic factor novel prevent programs promoter recombinase relating to nervous system second messenger selective expression

项目摘要

DESCRIPTION (provided by applicant): Understanding how the normal brain develops and what goes wrong in disease is fundamental for designing better ways to prevent congenital diseases, and to treat degenerative disorders marked by neuronal loss. Of particular relevance to this application, there is a growing recognition that heterotrimeric G proteins are critical for formation and maintenance of the brain. They produce bifurcating signals in the form of a GTP- subunit and a dimer that regulate phospholipases, adenylyl cyclases, and ion channels to produce the "second messengers" responsible for modulating many neuronal processes. The current challenge is to relate the individual G-protein subtypes to their regulation of particular processes. Both expression and functional evidence suggest the Gng5 gene encoding the G-protein gamma5 subunit plays a critical role in modulating proliferation, migration, or differentiation. Gng5 is preferentially expressed in neural progenitor cells. Moreover, we have shown that global deletion of Gng5 causes microcephaly. However, the information that can be obtained from studying the global knockout mice has been limited by their early embryonic lethality resulting from a cardiac defect. Consistent with the stated purpose of the R03 mechanism, this application proposes to develop a conditional knockout mouse model in which Gng5 is specifically deleted in neural progenitor cells. This will be accomplished by crossing mice carrying two floxed Gng5 alleles with transgenic mice expressing Cre-recombinase under control of the nestin promoter. Subsequently, histological analyses of conditional knockout brains will be performed to identify how loss of the G-protein ?5 subunit affects cortical size and organization, while molecular strategies will be used to elucidate any underlying defects in proliferation, migration, or differentiation of neural progenitor cells. Revealing the signaling pathways requiring the G-protein ?5 subunit that is responsible for neural progenitor cell expansion, migration, or differentiation may provide a molecular basis for the future development of effective strategies to prevent congenital disorders and treat neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: To improve the health of the American people, the goal of both NINDS and NICHD are to gain a better understanding of how the normal brain develops, and to translate these discoveries into better strategies to prevent congenital disorders, and to more effectively treat neurodegenerative disorders. This R03 application addresses both goals by providing a novel mouse model for studying how heterotrimeric G proteins are involved in formation and maintenance of brain. This resource will have inherent value to both the neuroscience and development communities.

描述（由申请人提供）：了解正常大脑如何发育以及疾病中出现的问题是设计更好的方法来预防先天性疾病和治疗以神经元丧失为标志的退行性疾病的基础。与此应用特别相关的是，越来越多的人认识到异源三聚体G蛋白对