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: 8420460
• 负责人: QIANG LU
• 金额: $ 35.46万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420460
• 关键词: Adult; Behavioral; Binding; Biological Assay; Biological Models; Brain; Brain Diseases; Candidate Disease Gene; Cerebral cortex; Databases; Defect; Development; Diagnostic; Electroporation; Epigenetic Process; Equilibrium; Etiology; Event; Family; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Mutation; Genes; Genetic; 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; gain of function; genetic analysis; in utero; in vivo; innovation; insight; loss of function; malformation; nerve stem cell; neurogenesis; novel; novel strategies; progenitor; public health relevance; 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）：神经干/祖细胞研究为了解病因和开发许多发育性和行为性脑部疾病和脑癌的潜在治疗方法提供了新途径。该研究的核心是干/祖细胞的两个关键状态（自我更新状态和分化状态）如何通过发育和成年生活中的内在和外在机制来维持微妙的平衡，因为神经干/祖细胞这种稳态的缺陷会导致大脑畸形，甚至可能导致肿瘤形成。过去十年的研究迄今为止已经发现了数十个通过促进自我更新或刺激分化而对这种调节发挥重要作用的基因，然而，这一进展仅代表我们对这一基本干细胞生物学问题的理解的开始。在本申请中，我们建议系统地、全面地表征神经祖细胞中特异性表达的基因，并利用这些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，通过了解这一过程中涉及的相关因素，我们将能够更好地阐明有助于确定神经祖细胞自我更新和分化状态的机制。为此，我们开发了一种新型遗传双报告系统，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系后代。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，以识别差异表达的基因。通过识别和表征这些差异表达基因，我们期望揭示神经祖细胞稳态的关键调节因子。这最终将有助于了解神经祖细胞中分子相互作用的平衡是什么以及如何引导自我更新和分化之间的平衡，以及个体分子轴的失调如何可能导致脑部疾病的特定病理状况。