REGULATION OF CEREBELLAR DEVELOPMENT BY RETINOIC ACID

我的长期目标是在中国有一个成功的学术研究生涯 视黄醇神经生物学领域。这个区域是我帖子的延伸- 维甲酸(RA)在发育中的作用的博士研究 视网膜上的。我的工作为我提供了新的工具和技术 意愿用来阐明维甲酸新陈代谢的新方面。这个 维甲酸是一种必需的营养补充剂 生长、繁殖和视力。RA，维生素A的活性代谢物， 越来越多地用于癌症和皮肤病的临床治疗 疾病。接触维甲酸同系物甚至可能来自杀虫剂 比如甲氧基丁二烯。由于RA过量，存在潜在的危险 神经毒性，特别是在儿童中，也是最 鉴定出致畸物质。它的有害行为是通过 RA代谢正常模式的失调和中枢 神经系统(CNS)特别敏感。这项建议的目的是 就是绘制发育中的中枢神经系统中维甲酸代谢的路径图。我 将专注于大脑的单个区域的发展，即 小脑，允许直截了当、连贯的研究计划 发展起来的。小脑是中枢神经系统的一个区域，在那里发育和 功能可以通过RA代谢的紊乱而被打乱。 胚胎意外接触痤疮药物Acanane(R)表明 人类的小脑发育很容易受到正常的干扰 类风湿关节炎的分布格局。对系统性应用的高度敏感性 维甲酸表明发育中的小脑是天然的 倾向于对内源性合成的RA有反应。L现在提议 研究维甲酸代谢和信号转导的途径 在发育中的小脑中，以确定这些因素是如何 干扰这些过程会扰乱发育。L将得到协助 由施莱弗中心的几位脂类分析领域的专家 和分子生物学。最初，L将同时使用小说和传统 研究正常小脑发育过程中RA代谢的技术， 然后研究体内的发育变化 这类通道的干扰。为了方便今后的工作， 人类的小脑异常L也会孤立人类 小鼠维甲酸产生酶的同系物。

My long-range goal is to have a successful academic research career in the field of retinoid neurobiology. This area is an extension of my post- doctoral research on the role of retinoic acid (RA) in the development of the retina. My work has provided new tools and techniques which I intend to use to elucidate new facets of retinoid metabolism. The retinoid vitamin A is an essential nutritional supplement required for growth, reproduction and sight. RA, the active metabolite of vitamin A, is increasingly used in the clinical treatment of cancers and skin diseases. Exposure to retinoid homologues may even come from insecticides such as methoprene. Potential hazards exist since RA, in excess, is neurotoxic, particularly in children, and is also one of the most teratogenic substances identified. Its pernicious actions are through the disregulation of the normal patterns of RA metabolism and the central nervous system (CNS) is particularly sensitive. The aim of this proposal is to map the pathways of retinoid metabolism in the developing CNS. I will focus on the development of a single region of the brain, the cerebellum, allowing a straightforward, coherent research program to be developed. The cerebellum is a region of the CNS in which development and function can be disrupted through disturbances in RA metabolism. Accidental exposure of embryos to the acne drug Acutane(R) has shown that human cerebellar development is vulnerable to a disruption in the normal pattern of RA distribution. A high susceptibility to systemically applied retinoic acid indicates that the developing cerebellum is naturally disposed to respond to endogenously synthesized RA. l now propose to investigate the pathways of retinoid metabolism and signal transduction in the developing cerebellum in order to determine how factors that interfere with these processes disrupt development. l will be assisted by several experts at the Shriver Center in the fields of lipid analysis and molecular biology. Initially, l will use both novel and traditional techniques to study RA metabolism during normal cerebellar development, then investigate the developmental changes that result from in-vivo disturbances of such pathways. In order to facilitate future work on cerebellar abnormalities in humans l will also isolate the human homologue of the murine retinoic-acid generating enzyme.