Factors Influencing Shh Signaling in the Forebrain

描述（由申请人提供）：这项工作的主要目的是研究大脑发育的机制。具体来说，这些研究集中在信号蛋白Shh和调节其活性的新型蛋白质上。Shh通路中的许多蛋白质已被证明在特定的临床疾病中发挥不可或缺的作用。Shh基因本身的突变会导致前脑无裂畸形。Shh需要C-末端胆固醇部分进行信号传导的发现支持其参与由遗传或环境诱导的胆固醇缺乏引起的肢体，CNS和面部畸形。从Shh N-末端脂肪酰化机制的拟议工作来看，影响该过程调控的基因突变也可能导致类似于功能丧失Shh突变体的疾病。除了发育缺陷外，patched或gli（Shh通路中的基因）的突变也会导致肿瘤形成。因此，对影响Shh信号传导的机制的研究将增加我们对该途径中断导致的多种疾病状态的理解。这些研究的主要目标是确定特定的前脑神经元是如何产生的。虽然已知将胎儿组织移植到患有神经变性疾病如亨廷顿氏病和帕金森氏病的人中可以是治疗性的，但是供体组织的可用性的缺乏通常限制了该方法。鉴于亨廷顿病和帕金森病都是由特定神经元群体的变性引起的，这项拟议的工作可能会揭示对这些神经元再生重要的因素。最后，正如这些研究中提出的那样，从使用复制缺陷病毒和超声引导胚胎注射中吸取的教训可以应用于完善基因治疗工具，特别是定义外源性药物在拯救特定疾病中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.