Molecular Genetic Analysis of Mammalian Neuronal differentiation

哺乳动物神经元分化的分子遗传学分析

• 批准号: 8804956
• 负责人: QIANG LU
• 金额: $ 36.75万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804956
• 关键词: Adult; Behavioral; Binding; Biological Assay; Biological Models; Brain; Brain Diseases; Candidate Disease Gene; Cerebral cortex; DNA Sequence Alteration; Databases; Defect; Development; Diagnostic; Electroporation; Epigenetic Process; Equilibrium; Etiology; Event; Family; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Health; Homeostasis; Human; Individual; Lead; Life; Logic; Maintenance; Malignant neoplasm of brain; Mediating; Methods; Molecular; Molecular Genetics; Molecular Profiling; Mus; Neuronal Differentiation; Neurons; Positioning Attribute; Process; Receptor Protein-Tyrosine Kinases; Regenerative Medicine; Regulation; Reporter; Research; Resources; Role; Signaling Molecule; Specific qualifier value; Staging; Stem cells; System; Work; base; brain malformation; cell fate specification; comparative; design; differential expression; gain of function; genetic analysis; genetic approach; in utero; in vivo; innovation; insight; loss of function; malformation; nerve stem cell; neurogenesis; novel; novel strategies; progenitor; receptor; relating to nervous system; self-renewal; stem; stem cell biology; therapeutic target; transcription factor; tumor

DESCRIPTION (provided by applicant): Neural stem/progenitor cell study offers novel avenues for understanding the etiology and for developing potential treatment of many developmental and behavioral brain disorders and brain cancers. At the center of the study is how a delicate balance between the two key states of stem/progenitor cells, the self-renewal state and differentiation state, are maintained by intrinsic and extrinsic mechanisms in development and in adult life, because a defect in this homeostasis of neural stem/progenitor cells causes malformation of the brain and may even lead to tumor formation. Research over the past decade has thus far uncovered dozens of genes that are important for this regulation by either promoting self-renewal or stimulating differentiation, however, this progress represents only the beginning of our understanding on this fundamental stem cell biology issue. In this application, we propose to systematically and comprehensively characterize genes that are specifically expressed in neural progenitor cells and use this information to further identify causal factors crucial for the control of neural progenitor homeostasis. Our rationale is that by knowing the relevant factors involved in this process, we will be in a better position to elucidate the mechanisms that help specify the self-renewal and differentiation state of neural progenitor cells. To this end, we have developed a novel genetic two reporter system that enables isolation of endogenous neural progenitor cells and their direct progeny from the developing mouse brains. The purified neural progenitor cells and progeny will allow us to perform comparative gene expression analyses to identify differentially expressed genes. By identifying and characterizing these differentially expressed genes, we expect to uncover key regulators of neural progenitor homeostasis. This will ultimately help understand what and how equilibrium of molecular interactions in neural progenitor cells guides the balance between self-renewal and differentiation and how dysregulation in individual molecular axis may lead to a particular pathological condition in brain disorders.

描述（由申请人提供）：神经茎/祖细胞研究提供了新的途径，以理解病因和开发许多发育和行为脑部疾病和脑癌的潜在治疗。研究的中心是如何通过在发育和成人生活中的内在和外在机制维持的茎/祖细胞的两个关键状态（自我更新状态和分化状态）之间的微妙平衡，因为这种神经茎/祖细胞的缺陷会导致脑部畸形的缺陷，甚至会导致脑部畸形，甚至可能导致肿瘤形成。在过去的十年中，迄今为止，通过促进自我更新或刺激分化而发现了数十种对这种调节很重要的基因，但是，这种进步仅代表了我们对这个基本干细胞生物学问题的理解的开始。在此应用中，我们建议系统地和全面地表征在神经祖细胞中特异性表达的基因，并使用此信息进一步识别对控制神经祖细胞稳态至关重要的因果因素。我们的理由是，通过了解此过程中涉及的相关因素，我们将有更好的位置阐明有助于指定神经祖细胞的自我更新和分化状态的机制。为此，我们开发了一种新型的遗传两个报告基因系统，该系统能够从发育中的小鼠大脑中分离内源性神经祖细胞及其直接后代。纯化的神经祖细胞和后代将使我们能够进行比较基因表达分析以鉴定差异表达的基因。通过识别和表征这些差异表达的基因，我们希望发现神经祖细胞稳态的关键调节剂。这最终将有助于了解神经祖细胞中分子相互作用的什么和平衡如何指导自我更新和分化之间的平衡以及单个分子轴的失调如何导致脑疾病中特定的病理状况。