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

• 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
• 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

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(申请人提供)：周围神经病是一组疾病，其特征是四肢运动功能受损和感觉丧失。一般人群中有2%-8%的人患有周围神经病变，这使得这些疾病成为一个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编码对髓鞘雪旺细胞至关重要的蛋白质的基因突变。雪旺细胞是一种隔离周围神经轴突并为其提供营养因子的细胞群体。目前，我们对雪旺细胞发育和动态平衡所涉及的转录层次结构的了解非常有限。含SRY-box基因10(Sox10)编码一种转录因子，对雪旺细胞的发育和功能至关重要。重要的是，Sox10基因和受Sox10基因调控的基因突变与脱髓鞘周围神经病有关。因此，新的Sox10靶基因的识别和鉴定将为脱髓鞘周围神经病提供更多的候选基因和关于雪旺细胞生物学的关键知识。为此，我们将：(1)在全基因组范围内鉴定髓鞘雪旺细胞中的Sox10靶基因；(2)确定Sox10是否是髓鞘雪旺细胞中两个新的靶基因(SH3KBP1和BCAS3)表达所必需的；以及(3)鉴定SH3KBP1和BCAS3在髓鞘雪旺细胞中的功能。 与公共健康相关：雪旺细胞是周围神经的关键组成部分，周围神经是手脚活动和感觉必不可少的结构。令人惊讶的是，人们对雪旺细胞的基因调控知之甚少。这项建议的主要目标是通过全基因组识别雪旺细胞中表达的新基因和蛋白，并确定它们对雪旺细胞功能的贡献，来解决这种缺乏知识的问题。这些研究将提供有关周围神经功能和相关人类疾病的关键信息，如周围神经病和多发性硬化症。