Neurotrophins and the Myelination Program of the PNS

描述(申请人提供)：已经发现了一些导致周围神经系统脱髓鞘疾病的基因。探索这些基因改变引起的脱髓鞘机制也阐明了髓鞘形成的分子机制。例如，外周髓鞘蛋白22(PMP22)基因的突变似乎会不同地改变PMP22蛋白的相互作用，进而改变其运输模式。这些研究的一个分支是发现脑源性神经营养因子(BDNF)和神经营养因子-3(NT3)除了是感觉神经元的生存因素外，也是髓鞘形成过程的媒介。在这项拟议的研究中，将确定神经营养因子受体的身份和位置，这些受体负责BDNF和NT3的作用。这些实验包括使用功能阻断抗体或受体抗体，以及选择性地与trk受体或p75NTR结合的神经营养素突变体。受体的定位将通过原位杂交进行探测。两个互补的髓鞘系统将被使用，一个在感觉神经元和雪旺细胞的共同培养中，另一个在发育中的坐骨神经中。共培养中确定的受体的表达将在体内系统中以及缺乏适当的神经营养因子受体或神经营养因子的存活动物的发育中的坐骨神经中进行探索。除了确定另一个参与髓鞘形成的配体-受体系统外，这些数据还可能有助于考虑神经营养素在外周脱髓鞘疾病中的治疗应用。

DESCRIPTION (provided by applicant): A number of genes have been discovered that are responsible for the demyelinating diseases of the peripheral nervous system. Exploring the mechanisms of demyelination caused by alterations in these genes also illuminates the molecular mechanisms of myelination. For example, it appears that mutations in the peripheral myelin protein 22 (PMP22) gene differentially alter the interactions of the PMP22 protein and in turn alter its trafficking pattern. An offshoot of these studies was the discovery that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3), besides being survival factors for sensory neurons, are also mediators of the myelination process. In this proposed study the identity and location of the neurotrophin receptors that are responsible for the actions of BDNF and NT3 will be determined. The experiments involve the use of function blocking antibodies or receptor antibodies and of neurotrophin mutants that bind selectively to either the trk receptors or to the p75NTR. Location of the receptors will probed by in situ hybridization. Two complementary myelination systems will be used, one in cocultures of sensory neurons and Schwann cells and the other in the developing sciatic nerve. The expression of the receptors identified in cocultures will be explored in the in vivo system and in the developing sciatic nerve of viable animals deficient in appropriate neurotrophin receptors or neurotrophins. Besides identifying one more ligand-receptor system involved in myelination the data may also aid in considering the therapeutic application of neurotrophins in the peripheral demyelinating disease.