GPR56 信号传导对皮质发育的调节-猫眼课题宝

GPR56 信号传导对皮质发育的调节

批准号：

7370121

负责人：

Xianhua Piao

金额：

$33.95万

依托单位：

BOSTON CHILDREN'S HOSPITAL

依托单位国家：

美国

项目类别：

财政年份：

2007

资助国家：

美国

项目状态：

已结题

起止时间：

2007-12-15 至 2012-11-30

来源：

https://reporter.nih.gov/project-details/7370121

关键词：

Address Affect Basal lamina Basement membrane Bilateral Binding Brain CD81 gene Cell Proliferation Congenital cerebellar hypoplasia Cortical Dysplasia Cortical Malformation Defect Development Developmental Process Diagnosis Disease Embryo Epilepsy Exhibits Family Functional disorder G-Protein-Coupled Receptors Generations Genes Goals Histopathology Human Individual Integrins Knock-out Knockout Mice Laminin Lead Ligands Localized Mediating Mental Retardation Messenger RNA Microcephaly Microgyria Molecular Mus Mutant Strains Mice Mutation Neuraxis Neuroglia Neurons Pathogenesis Pathology Patients Pattern Phenotype Play Process Proteins Publishing Radial Regulation Regulator Genes Research Role Seizures Signal Pathway Signal Transduction Site Specimen Surface Syndrome Testing Transgenic Mice Ventricular base brain malformation design human GPRC5C protein intracellular protein transport loss of function mutation member migration mouse model mutant nerve stem cell nervous system disorder novel positional cloning promoter protein transport trafficking white matter

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DESCRIPTION (provided by applicant): Mutations of regulatory genes in the developing central nervous system are frequently associated with human neurological diseases. Disorders in neuronal cell proliferation, migration, and lamination, in particular, lead to mental retardation and epilepsy. Our long-term goal is to study the molecular mechanisms that underlie cortical development and their related neurological disorders. Using positional cloning, we recently demonstrated that loss-of-function mutation in GPR56, an orphan G protein-coupled receptor (GPCR), causes a specific cortical malformation known as bilateral frontoparietal polymicrogyria (BFPP). Identification of GPR56 as a causative gene of BFPP leads to the specific hypothesis of this application that the signaling pathway of GPR56 is crucial in regulating cortical development. Our hypothesis is based on published and preliminary observations that: (1) mutations in GPR56 cause a specific human cortical malformation, BFPP; (2) mouse Gpr56 mRNA is expressed mainly in neuronal progenitor cells, suggesting that it may play an important role in cortical development and patterning; and (3) Gpr56 knockout causes cortical dysplasia in mice; (4) GPR56 functions synergistically with 13 integrin and Gpr56/13 integrin double knockout mice have more severe and extensive cortical dysplasia. Based on these observations, the experimental focus of this proposal is on the functional analysis of GPR56 in mouse models. The specific aims are to: (1) delineate the pathogenesis of BFPP; (2) investigate the potential interaction of GPR56 and 13 integrin; and (3) study GPR56 protein trafficking. Abnormal brain development frequently causes human neurological disorders such as mental retardation and seizures. The gene GPR56 is important in brain development, and its mutation causes brain malformations in humans. The proposed research is designed to study GPR56-mediated brain development and its related pathophysiology.

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