Factors Influencing Shh Signaling in the Forebrain

描述(申请人提供)：这项工作的主要目的是研究大脑发育的机制。具体地说，这些研究集中在信号蛋白Shh和调节其活性的新蛋白上。Shh途径中的许多蛋白质已被证明在特定的临床疾病中起着不可或缺的作用。Shh基因本身的突变会导致全前脑畸形。Shh需要C-末端的胆固醇部分来传递信号，这一发现支持Shh参与肢体、中枢神经系统和面部畸形，这些畸形是由遗传或环境诱导的胆固醇缺乏引起的。从Shh N-末端脂肪酰化机制的拟议工作来看，影响这一过程调控的基因突变(S)很可能也会导致类似于功能丧失的Shh突变体的疾病。除了发育缺陷，补丁或GLI(Shh途径中的基因)突变也会导致肿瘤的形成。因此，研究影响Shh信号转导的机制将增加我们对该通路中断所导致的多种疾病状态的理解。这些研究的一个主要目标是确定特定的前脑神经元是如何产生的。虽然众所周知，将胎儿组织移植到患有亨廷顿氏症和帕金森氏症等神经退行性疾病的人类体内可以起到治疗作用，但供体组织的缺乏往往会限制这种方法。鉴于亨廷顿病和帕金森病都是由特定神经元群体的退化引起的，这项拟议的工作可能会揭示对这些神经元的再生至关重要的因素。最后，从使用复制缺陷病毒和超声波引导的胚胎注射中吸取的经验教训，如这些研究中所建议的，可用于完善基因治疗工具，特别是确定外源性药物在拯救特定疾病时的时机和剂量之间的关系。

DESCRIPTION (provided by applicant): The major purpose of this work is to investigate mechanisms governing brain development. Specifically, these studies focus on the signaling protein Shh, and novel proteins that regulate its activity. Many of the proteins in the Shh pathway have been shown to play an integral role in specific clinical disorders. Mutations in the Shh gene itself cause holoprosencephaly. The finding that Shh requires a C-terminal cholesterol moiety for signaling supports its involvement in limb, CNS, and facial malformations that result from genetic or environmentally-induced cholesterol deficiency. From the proposed work on the mechanism of Shh N-terminal fatty-acylation, it is likely that mutation(s) of genes affecting the regulation of this process will also result in diseases similar to loss-of-function Shh mutants. In addition to developmental defects, mutations in patched or gli (genes in the Shh pathway) result in tumor formation. Thus, investigation of the mechanisms influencing Shh signaling will increase our understanding of a multitude of disease states that result from the disruption of this pathway. A major goal of these studies is to determine how specific forebrain neurons are generated. While it is known that grafting of fetal tissue into humans suffering from neurodegenerative disorders such as Huntington's and Parkinson's disease can be therapeutic, the lack of availability of donor tissue often limits this method. Given that both Huntington's and Parkinson's disease result from the degeneration of specific neuronal populations, the proposed work may reveal factors important to the regeneration of such neurons. Lastly, lessons learned from the use of replication-defective viruses and ultrasound-guided embryonic injections, as proposed in these studies, can be applied to perfecting tools for gene therapy, specifically to define the relationship between the timing and dose of exogenous agents in rescuing a particular disease.