SONIC HEDGEHOG AND CYCLOPAMINE INDUCED HOLOPROSENCEPHALY

描述：（改编自申请人的摘要）环巴胺是一种 从沙漠玉米百合中分离的致畸甾体生物碱。 脊椎动物胚胎原肠胚形成前后暴露于环巴胺 发展出类似人类的大脑和颅面畸形， 前脑无裂畸形 前脑无裂畸形也与大脑皮层缺失有关。 Sonic Hedgehog基因的功能突变和 胆固醇代谢 音速刺猬在脊索中表达， 编码一种指导模式形成的蛋白质（SHH 在神经管的腹侧部分 SHH合成之后是 自身蛋白水解事件，由此氨基末端裂解产物被 附着在胆固醇上，从而附着在细胞的外表面。 由于环巴胺在结构上与胆固醇相似， 假设环巴胺干扰SHH介导的信号 转导 初步数据支持环巴胺阻断 SHH自动蛋白水解加工。 环巴胺的作用可能是直接的 阻断SHH与胆固醇的结合或间接抑制 胆固醇生物合成 降胆固醇药物（BM-15.766，AY-9944） 其干扰胆固醇生物合成， 方面的影响. 这个假设将通过解决几个目标来检验。 首先，环巴胺和降胆固醇剂对 鸟类和仓鼠神经管中SHH介导的模式化事件 胚胎将被确定。 预计这些代理中的每一个都将 在神经管中诱导异常的形态和生化模式， 这与在SHH缺陷胚胎中观察到的结果相当。 致畸 各种天然和合成的结构类似物的潜力 环巴胺也将被检查，各种致畸潜力 环巴胺的天然和合成结构类似物将被检查 并且所有这些药剂的致畸性将与它们的 对SHH自身蛋白水解和胆固醇生物合成的影响， 体外 目标是阐明导致这些疾病的分子事件， 环巴胺和相关甾体生物碱的致畸作用，以及 表征介导这些的致畸剂的结构特性 方面的影响. 拟议的研究可能具有重要的环境健康 由于甾体生物碱被发现在许多农业 产品.

DESCRIPTION: (Adapted from the Applicant's Abstract) Cyclopamine is a teratogenic steroidal alkaloid which was isolated from the desert corn lily. Vertebrate embryos exposed to cyclopamine around the period of gastrulation develop brain and craniofacial malformations analogous to humans with holoprosencephaly. Holoprosencephaly has also been associated with loss of function mutations in the Sonic Hedgehog gene and abnormalities in cholesterol metabolism. Sonic Hedgehog is expressed in the notochord and prechordal plate and encodes a protein (SHH) that directs pattern formation in the ventral portion of the neural tube. SHH synthesis is followed by an autoproteolytic event whereby the amino-terminal cleavage product is attached to cholesterol, thereby affixed to the outer surface of the cell. Because cyclopamine is structurally similar to cholesterol, it is hypothesized that cyclopamine interferes with SHH-mediated signal transduction. Preliminary data support a model in which cyclopamine blocks SHH autoproteolytic processing. The effect of cyclopamine might be direct disruption of SHH association with cholesterol or indirect suppression of cholesterol biosynthesis. Hypocholesterolemic drugs (BM-15.766, AY-9944) which interfere with cholesterol biosynthesis produce similar teratogenic effects. The hypothesis will be tested by addressing the several aims. First, the effects of cyclopamine and hypocholesterolemic agents on SHH-mediated patterning events in the neural tubes of avian and hamster embryos will be determined. It is expected that each of these agents will induce abnormal morphological and biochemical patterns in the neural tube, comparable to those observed in SHH-deficient embryos. The teratogenic potential of various natural and synthetic structural analogues of cyclopamine will also be examined and the teratogenic potential of various natural and synthetic structural analogues of cyclopamine will be examined and the teratogenicity of all these agents will be correlated with their effects on SHH autoproteolysis and cholesterol biosynthesis, as measured in vitro. The goals are to elucidate the molecular events which underly the teratogenic effects of cyclopamine and related steroidal alkaloids, and to characterize the structural properties of teratogens which mediate these effects. The proposed research may have important environmental health implications since steroidal alkaloids are found in many agricultural products.