Dissection of genetic pathways critical for myelinating Schwann cell development

解析对有髓鞘雪旺细胞发育至关重要的遗传途径

基本信息

批准号：
8081921
负责人：
Anthony Antonellis
金额：
$ 29.32万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8081921
关键词：
Address Affect Animal Model Axon Binding Proteins Binding Sites Boxing Candidate Disease Gene Cell Adhesion Cell physiology Cells Cellular biology Chickens Critical Pathways Data Development Disease Dissection Distal Embryo Enhancers Esthesia Gene Expression Gene Expression Regulation Gene Proteins Gene Targeting General Population Genes Genetic Genomic Segment Genomics Goals Hand Homeostasis Human In Vitro Inherited Knock-out Knowledge Limb structure Motor Multiple Sclerosis Mus Muscle Weakness Mutate Mutation Patients Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Phosphotransferases Pilot Projects Population Proteins Public Health RNA Reporter Genes SH3 Domains Schwann Cells Sensory Sequence Analysis Staging Structure Testing Tissues Vertebrates Zebrafish adapter protein cell motility comparative foot genome wide association study genome-wide human disease in vivo insight malignant breast neoplasm mutant novel transcription factor

项目摘要

DESCRIPTION (provided by applicant): Peripheral neuropathies are a group of diseases characterized by impaired motor function and sensory loss in the extremities. Between 2-8% of the general population is affected with a peripheral neuropathy, making these diseases a significant public health concern. More than 80% of patients with inherited peripheral neuropathy carry mutations in genes encoding proteins critical for myelinating Schwann cells-a cell population that insulates and provides trophic factors to peripheral nerve axons. Currently, we have a very limited understanding of the transcriptional hierarchies involved in Schwann cell development and homeostasis. The SRY-box containing gene 10 (SOX10) encodes a transcription factor that is essential for Schwann cell development and function. Importantly, mutations in SOX10 and in loci regulated by SOX10 have been implicated in demyelinating peripheral neuropathies. Thus, the identification and characterization of novel SOX10 target loci will provide additional candidate genes for demyelinating peripheral neuropathies and key knowledge regarding Schwann cell biology. Toward this, we will: (1) Perform genome-wide identification of SOX10 target loci in myelinating Schwann cells; (2) Determine if SOX10 is necessary for the expression of two novel target genes (SH3KBP1 and BCAS3) in myelinating Schwann cells; and (3) Characterize the function of SH3KBP1 and BCAS3 in myelinating Schwann cells. PUBLIC HEALTH RELEVANCE: Schwann cells are a critical component of peripheral nerves-structures essential for mobility and sensation in the hands and feet. Remarkably little is known about gene regulation in Schwann cells. The major goal of this proposal is to address this lack of knowledge through genome-wide identification of novel genes and proteins expressed in Schwann cells and determining how they contribute to Schwann cell function. These studies will provide key information on the function of peripheral nerves and associated human diseases such as peripheral neuropathy and multiple sclerosis.

描述（由申请人提供）：周围神经病是一组以四肢运动功能受损和感觉丧失为特征的疾病。 2-8% 的普通人群患有周围神经病，使这些疾病成为重要的公共卫生问题。超过 80% 的遗传性周围神经病患者携带对髓鞘化雪旺细胞至关重要的蛋白质基因突变，雪旺细胞是一种隔离周围神经轴突并为周围神经轴突提供营养因子的细胞群。目前，我们对雪旺细胞发育和稳态中涉及的转录层次结构的了解非常有限。含有基因 10 (SOX10) 的 SRY 盒编码对雪旺细胞发育和功能至关重要的转录因子。重要的是，SOX10 和 SOX10 调节的基因座的突变与脱髓鞘性周围神经病有关。因此，新的 SOX10 靶位点的鉴定和表征将为脱髓鞘周围神经病提供额外的候选基因以及有关雪旺细胞生物学的关键知识。为此，我们将：（1）对有髓鞘雪旺细胞中的 SOX10 靶位点进行全基因组鉴定； (2) 确定SOX10对于有髓鞘雪旺细胞中两个新靶基因（SH3KBP1和BCAS3）的表达是否是必需的； (3) 表征 SH3KBP1 和 BCAS3 在髓鞘雪旺细胞中的功能。公共卫生相关性：雪旺细胞是周围神经结构的重要组成部分，对于手脚的活动和感觉至关重要。人们对雪旺细胞中的基因调控知之甚少。该提案的主要目标是通过全基因组鉴定雪旺细胞中表达的新基因和蛋白质并确定它们如何促进雪旺细胞功能来解决这种知识的缺乏。这些研究将提供有关周围神经功能和相关人类疾病（例如周围神经病和多发性硬化症）的关键信息。