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：
8234039
负责人：
Anthony Antonellis
金额：
$ 30.61万
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/8234039
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 public health relevance transcription factor

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 public health relevance transcription factor

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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）：周围神经病是一组疾病，其特征是运动功能受损和四肢的感觉丧失。在2-8％的一般人群中受到周围神经病的影响，使这些疾病成为重大的公共卫生问题。超过80％的遗传性周围神经病患者携带突变的基因，这些基因编码蛋白质至关重要的蛋白质对骨髓的schwann细胞 - A细胞群，可绝缘并为周围神经轴突提供营养因子。目前，我们对Schwann细胞开发和稳态涉及的转录层次结构的理解非常有限。包含基因10（SOX10）的SRY-box编码对于Schwann细胞发育和功能至关重要的转录因子。重要的是，Sox10和受Sox10调节的基因座的突变与外周神经病有关。因此，新型Sox10靶基因座的鉴定和表征将提供其他候选基因，用于脱髓鞘神经病以及有关Schwann细胞生物学的关键知识。在此方面，我们将：（1）对髓生成schwann细胞中的Sox10靶基因座进行全基因组鉴定；（2）确定Sox10是否对于髓鞘的Schwann细胞中两个新型靶基因（SH3KBP1和BCAS3）表达是否需要；（3）表征SH3KBP1和BCAS3在髓鞘的Schwann细胞中的功能。公共卫生相关性：Schwann细胞是外围神经结构的关键组成部分，对于手和脚的移动性和感觉必不可少。关于雪旺细胞中的基因调节知之甚少。该提案的主要目的是通过对Schwann细胞中表达的新基因和蛋白质的全基因组鉴定来解决这种缺乏知识，并确定它们如何对Schwann细胞功能做出贡献。这些研究将提供有关周围神经和相关人类疾病（如周围神经病和多发性硬化症）功能的关键信息。