Neurotrophins and the Myelination Program of the PNS

描述（由申请人提供）：已发现许多基因与周围神经系统脱髓鞘疾病有关。探索由这些基因的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，外周髓磷脂蛋白22（PMP 22）基因的突变似乎差异性地改变了PMP 22蛋白的相互作用，进而改变了其运输模式。这些研究的一个分支是发现脑源性神经营养因子（BDNF）和神经营养素-3（NT 3）除了是感觉神经元的存活因子外，也是髓鞘形成过程的介质。在这项拟议的研究中，将确定负责BDNF和NT 3作用的神经营养因子受体的身份和位置。实验涉及使用功能阻断抗体或受体抗体和选择性结合trk受体或p75 NTR的神经营养因子突变体。通过原位杂交探测受体的位置。将使用两种互补的髓鞘形成系统，一种用于感觉神经元和许旺细胞的共培养物，另一种用于发育中的坐骨神经。将在体内系统和缺乏适当神经营养因子受体或神经营养因子的存活动物的发育坐骨神经中探索共培养物中鉴定的受体的表达。除了确定一个参与髓鞘形成的配体-受体系统外，这些数据还有助于考虑神经营养因子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.