Cell Adhesion Molecules in CNS Development

中枢神经系统发育中的细胞粘附分子

• 批准号: 7454433
• 负责人: Ulrich Mueller
• 金额: $ 51.54万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454433
• 关键词: Adhesions; Affect; Alleles; Alzheimer' s Disease; Behavior Control; Binding; Binding Sites; Bromodeoxyuridine; CD29 Antigen; Cell Adhesion Molecules; Cell Cycle; Cell Cycle Progression; Cell Line; Cell Proliferation; Cell Proliferation Regulation; Cell Surface Receptors; Cell surface; Cells; Cerebellar cortex structure; Cerebellum; Cerebral cortex; Cerebrum; Complex; Data; Defect; Dementia; Development; Dimerization; Disease Progression; ECM receptor; Epilepsy; Erinaceidae; Event; Extracellular Matrix; Extracellular Matrix Proteins; Family; Genes; Genetic Transcription; Goals; Green Fluorescent Proteins; Health; Immunohistochemistry; In Vitro; Integrins; Knock-out; Label; Laminin; Lead; Ligands; Link; Maintenance; Maps; Mediating; Membrane Glycoproteins; Modeling; Molecular; Mus; Neuraxis; Neuroglia; Neurons; Numbers; Parkinson Disease; Pathogenesis; Pathway interactions; Pattern; Physiology; Population; Publishing; Recruitment Activity; Regulation; Role; Schizophrenia; Second Messenger Systems; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Staging; Structure; Testing; Therapeutic Agents; Ventricular; base; granule cell; in vivo; insight; migration; morphogens; nerve stem cell; nervous system development; nervous system disorder; precursor cell; receptor; research study; size

DESCRIPTION (provided by applicant): Developmental defects and degenerative changes that affect the central nervous system (CNS) lead to neurological disorders including dementia, epilepsy, schizophrenia, Parkinson's and Alzheimer's disease. An understanding of the mechanisms that regulate CNS development and function is expected to provide insights into the molecular pathogenesis of neurological disorders. The development and physiology of neurons is regulated by their interactions with neighboring cells and with extracellular matrix (ECM) molecules. The mechanisms by which receptors that mediate these interactions regulate neuronal development and health are poorly defined. Our long-term goal is to understand the mechanisms by which cell-cell and celI-ECM interactions regulate CNS development, maintenance, and function. We propose here to study ECM receptors of the beta1-integrin family in the CNS. We hypothesis that beta1-integrins are part of a regulatory network that controls cell cycle progression of cortical precursor cells in the CNS. To test our hypothesis, we will use genetically modified mice carrying floxed alleles, Cre, and GFP to analyze by BrdU labeling and immunohistochemistry defects in cell proliferation and differentiation of beta1 integrin-deficient CNS precursors in vivo, and after FACS sorting in vitro. Our preliminary data validate our hypothesis. They show that beta1-integrins regulate proliferation in neurogenic zones of the CNS. We expect that beta1 -integrins are part of the regulatory circuit that coordinates cell-cycle exit with differentiation and migration. The identification of the mechanisms that regulate these events is important to understand CNS development and disease progression, as well as to control the behavior of neural stem cells in order to use them as therapeutic agents.

描述（由申请人提供）： 影响中枢神经系统（CNS）的发育缺陷和退行性变化导致神经系统疾病，包括痴呆、癫痫、精神分裂症、帕金森病和阿尔茨海默病。对调节中枢神经系统发育和功能的机制的理解有望为神经系统疾病的分子发病机制提供见解。神经元的发育和生理学受其与邻近细胞和细胞外基质（ECM）分子的相互作用调节。介导这些相互作用的受体调节神经元发育和健康的机制尚不清楚。 我们的长期目标是了解细胞-细胞和细胞-ECM相互作用调节CNS发育、维持和功能的机制。我们建议在这里研究ECM受体的β 1-整联蛋白家族在中枢神经系统。我们假设β 1-整合素是控制中枢神经系统皮质前体细胞细胞周期进程的调控网络的一部分。为了验证我们的假设，我们将使用转基因小鼠携带floxed等位基因，Cre，和GFP分析BrdU标记和免疫组化缺陷的细胞增殖和分化的β 1整合素缺乏的CNS前体在体内，并在体外流式细胞仪分选后。我们的初步数据证实了我们的假设。他们表明β 1-整联蛋白调节中枢神经系统神经源性区域的增殖。 我们预期β 1-整合素是协调细胞周期退出与分化和迁移的调节回路的一部分。鉴定调节这些事件的机制对于理解CNS发育和疾病进展以及控制神经干细胞的行为以将其用作治疗剂是重要的。