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和调节其活性的新蛋白上。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着不可或缺的作用。Shh基因本身的突变会导致前脑畸形。Shh需要c端胆固醇片段来传递信号，这一发现支持其参与由遗传或环境诱导的胆固醇缺乏导致的肢体、中枢神经系统和面部畸形。从对Shh n端脂肪酰化机制的研究来看，可能影响这一过程调控的基因突变也会导致类似于Shh突变体功能丧失的疾病。除了发育缺陷，补丁或gli （Shh通路中的基因）的突变也会导致肿瘤的形成。因此，研究影响Shh信号传导的机制将增加我们对多种疾病状态的理解，这些疾病状态是由这一途径的破坏造成的。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。虽然已知将胎儿组织移植到患有神经退行性疾病（如亨廷顿氏病和帕金森病）的人体内可以治疗，但缺乏可用的供体组织往往限制了这种方法。考虑到亨廷顿氏病和帕金森病都是由特定神经元群的退化引起的，这项工作可能会揭示这些神经元再生的重要因素。最后，从这些研究中提出的复制缺陷病毒和超声引导胚胎注射的使用中吸取的经验教训可用于完善基因治疗工具，特别是用于确定外源药物在挽救特定疾病时的时间和剂量之间的关系。

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.