Factors Influencing Shh Signaling in the Forebrain

影响前脑 Shh 信号传导的因素

• 批准号: 7231351
• 负责人: Jhumku Dutt Kohtz
• 金额: $ 24.24万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231351
• 关键词: Acyltransferase; Affect; Binding; Brain; Brain Diseases; C-terminal; Cells; Cholesterol; Clinical; Data; Defect; Defective Viruses; Development; Disease; Disruption; Dorsal; Dose; Embryo; Event; Face; Fetal Tissue Transplantation; Gene Mutation; Genes; Genetic; Goals; Growth; Hand; Holoprosencephaly; Human; Huntington Disease; Injection of therapeutic agent; Investigation; Laboratories; Learning; Limb Development; Limb structure; Lipids; Mediating; Membrane; Methods; Modification; Mus; Mutation; N-terminal; Natural regeneration; Neural tube; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathway interactions; Pattern; Play; Population; Positioning Attribute; Process; Property; Prosencephalon; Proteins; Purpose; Regulation; Reporting; Role; Signal Transduction; Signaling Protein; Sonic hedgehog protein; Source; Structure; Therapeutic; Time; Tissue Donors; Tissues; Ultrasonography; Work; bone morphogenetic protein 7; cell type; design; fatty acylation; fly; gene therapy; inhibitor/antagonist; loss of function; malformation; mutant; novel; programs; receptor binding; research study; response; tool; tumor

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.

描述（由申请人提供）：这项工作的主要目的是研究控制大脑发育的机制。具体来说，这些研究重点关注信号蛋白 Shh 以及调节其活性的新型蛋白质。 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无裂畸形。 Shh 需要 C 末端胆固醇部分来进行信号传导，这一发现支持其参与由于遗传或环境诱导的胆固醇缺乏而导致的四肢、中枢神经系统和面部畸形。从Shh N-末端脂肪酰化机制的拟议工作来看，影响这一过程调节的基因突变也可能导致类似于功能丧失突变体的疾病。除了发育缺陷之外，patch 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 信号传导机制的研究将增加我们对由于该通路破坏而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舞蹈症和帕金森病等神经退行性疾病的人类体内可以起到治疗作用，但缺乏供体组织往往限制了这种方法。鉴于亨廷顿氏病和帕金森氏病都是由特定神经元群的退化引起的，因此拟议的工作可能揭示对此类神经元再生的重要因素。最后，正如这些研究中提出的，从使用复制缺陷型病毒和超声引导胚胎注射中吸取的经验教训可以应用于完善基因治疗工具，特别是确定外源性药物在拯救中的时间和剂量之间的关系。一种特定的疾病。