REGULATION OF CEREBELLAR DEVELOPMENT BY RETINOIC ACID

我的长期目标是在大学里有一个成功的学术研究生涯。 维甲酸神经生物学领域。这个领域是我职位的延伸- 维甲酸（RA）在发育中的作用的博士研究 的视网膜。我的工作提供了新的工具和技术， 拟用于阐明类维生素A代谢新方面。的 类维生素A是一种必需的营养补充剂， 生长繁殖和视力RA是维生素A的活性代谢产物， 越来越多地用于癌症和皮肤病的临床治疗 疾病接触类维生素A同系物甚至可能来自杀虫剂 例如甲氧普烯。由于RA过量， 神经毒性，特别是在儿童中，也是最重要的 发现致畸物质。其有害的行动是通过 RA代谢和中枢神经系统的正常模式失调 中枢神经系统（CNS）是非常敏感的。这项建议的目的是 是绘制发育中的中枢神经系统中类维生素A代谢的途径。我 将集中在大脑的一个区域的发展， 小脑，允许一个简单的，连贯的研究计划， 开发小脑是中枢神经系统的一个区域， 功能可通过RA代谢紊乱而被破坏。 胚胎意外接触痤疮药物Acutane（R）表明， 人类小脑的发育很容易受到正常 RA分布模式。对全身应用的高敏感性 视黄酸表明发育中的小脑是自然的， 倾向于对内源性合成的RA做出反应。我现在提议 探讨维甲酸代谢和信号转导途径 在发育中的小脑，以确定如何因素， 干扰这些过程会破坏发展。我会得到帮助 由Shriver中心的几位脂质分析领域的专家 和分子生物学。一开始，我会用传统的和新颖的 研究正常小脑发育过程中RA代谢的技术， 然后研究在体内 这些途径的干扰。为了便利今后关于 小脑异常我也会把人类 小鼠视黄酸生成酶的同源物。

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.