DETERMINING THE TRANSCRIPTIONAL REGULATION & CELL SIGNALING EVENTS THAT SHAPE TH

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 神经元的多样性对哺乳动物的神经系统功能至关重要。众所周知，特定神经元亚群的丧失或功能障碍会导致不同的神经系统疾病。帕金森氏病对人类健康具有破坏性和负面影响，是位于外侧中脑的黑质中脑多巴胺神经元变性的结果。黑质多巴胺神经元的损失导致无法正确控制运动。目前提出的治疗帕金森病的治疗线是使用基于胚胎干细胞或诱导多能干细胞的疗法。使用基于细胞的疗法的基本概念是将多巴胺神经元前体移植到帕金森病患者体内。测试这些方法的替代方法是将多巴胺神经元前体移植到中脑多巴胺神经元缺失的动物模型中。然而，一个显著的知识差距是，我们不了解黑质神经元在哺乳动物发育过程中是如何建立的，这转化为如何制造适当类型的多巴胺神经元的问题。这些缺陷需要解决，以设计有效的基于细胞的疗法来治疗帕金森病等神经退行性疾病。目前 没有有效指导干细胞获得最合适的命运以改善MbDA神经元特异性疾病的方案。我们已经确定了体内多巴胺神经元祖细胞库，并确定这些祖细胞在多巴胺神经元发育的多个关键步骤中表达基因Wnt 1。这项提议的目的是建立有助于多巴胺发育的表达Wnt 1的祖细胞的分子身份 神经元，并确定WNT信号如何指定MbDA神经元祖细胞。这项提案中的研究在细胞命运规范的概念与如何解决这一问题之间建立了联系。 建立了不同的神经元亚型。一个预期的结果是，我们将阐明用于控制复杂的祖细胞池的MbDA神经元亚型的发展的监管组件。这项应用的积极影响是，通过揭示亚型是如何分配的，我们将提供一种分子支架，可以有效地引导干细胞获得独特的MbDA身份。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A diverse array of neurons is essential for mammalian nervous system function. It is well known that the loss or dysfunction of specific subsets of neurons causes distinct neurological disorders. Parkinson's disease which has a devastating and negative impact on human health is the result of the degeneration of midbrain dopamine neurons of the substantia nigra, which are positioned in the lateral midbrain. The loss of substantia nigra dopamine neurons results in the inability to properly control movement. A current line of treatment proposed to treat Parkinson's disease is to use embryonic stem cell or induced pluripotent stem cell based therapy. The fundamental concept using cell based therapies is to transplant dopamine neuron precursors into patients with Parkinson's disease. A surrogate to test these approaches is transplant dopamine neuron precursors into animal models with midbrain dopamine neuron loss. However, a significant knowledge gap is that we do not understand how substantia nigra neurons are established during mammalian development, which translates into a problem of how to make the appropriate type of dopamine neuron. These deficits need to be addressed to design effective cell-based therapies to treat neurodegenerative diseases like Parkinson's disease. Currently there is no protocol to effectively instruct stem cells to acquire the most appropriate fate to ameliorate MbDA neuron-specific diseases. We have identified the dopamine neuron progenitor pool in vivo and determined that these progenitors express the gene Wnt1 during multiple critical steps for dopamine neuron development. The purpose of this proposal is to establish the molecular identity of Wnt1-expressing progenitors that contribute to developing dopamine neurons and to identify how WNT signaling specifies MbDA neuron progenitors. The studies in this proposal forge a link between the concept of cell fate specification and the problem of how distinct neuronal subtypes are established. An expected outcome is that we will elucidate regulatory components used to control the development of MbDA neuron subtypes from a complex progenitor pool. The positive impact of this application is that by uncovering how subtypes are allocated, we will provide a molecular scaffold that can be exploited to effectively guide stem cells to acquire a unique MbDA identity.