Neurofibromin, Ras and BDNF/trkB Signaling

描述(由申请人提供)： 神经纤维瘤病1(NF1)是一种常染色体显性遗传性疾病，由编码调节蛋白神经纤维蛋白(NF)的基因自发或遗传性功能丧失突变引起。NF1的特点是与周围神经系统相关的肿瘤(神经纤维瘤)和认知障碍，包括注意力缺陷、多动障碍和学习和记忆障碍。虽然NF1的遗传学基础已经确立，但导致NF1特有症状的生物学机制还不是很清楚。对转基因小鼠的研究表明，认知缺陷与神经纤维的GTP酶激活蛋白(GAP)活性的丧失有关。 本研究计划将重点研究神经丝GAP活性丧失导致认知功能障碍的细胞和分子机制，并将验证一种假说，即神经丝的正常功能是通过使G蛋白RAS失活来维持脑源性神经营养因子(BDNF)信号通路中的低基础活性。这一假说的预测是，NF1中NF1GAP活性的部分丧失导致BDNF信号通路中异常高的基础活性，导致BDNF3介导的正常学习和记忆的生理功能失调。这将通过检测缺乏神经营养因子的转基因神经元中的BDNF信号来进行测试。虽然已知BDNF通过其同源受体TrkB激活多个下游通路，但并不是所有下游通路都应该受到NF丢失的影响。免疫沉淀和蛋白质组学分析将用于鉴定和表征含有核因子和TrkB的功能信号复合体。 如果这一假说经受住了这一提议中概述的关键测试，BDNF/TrkB信号通路将成为药物或其他疗法的潜在靶点，这些疗法可以选择性地治疗NF1的认知症状；神经纤维瘤可能会通过单独的治疗策略得到更有效的治疗。除了验证这一假说，阐明核因子信号复合体的组成将为核因子的正常功能提供新的见解，并可能为治疗NF1的潜在分子靶点提供额外的线索。

DESCRIPTION (provided by applicant): Neurofibromatosis 1 (NF1) is an autosomal dominant disorder resulting from a spontaneous or inherited loss-of-function mutation in the gene encoding the regulatory protein, neurofibromin (NF). NF1 is characterized by tumors (neurofibromas) associated with the peripheral nervous system and by cognitive impairments including attention deficit hyperactivity disorder and learning and memory deficits. Although the genetic basis for NF1 has been established, the biological mechanisms by which loss of one copy of NF leads to the characteristic symptoms of the disease are not well understood. Studies with transgenic mice indicate that cognitive deficits are associated with the loss of GTPase activating protein (GAP) activity of NF. This research program will focus on the cellular and molecular mechanisms by which loss of NF GAP activity can lead to cognitive dysfunction and will test the hypothesis that the normal function of NF is to maintain low basal activity in the brain-derived neurotrophic factor (BDNF) signaling pathway by deactivating the G-protein, Ras. A prediction of this hypothesis is that partial loss of NF GAP activity in NF1 creates an abnormally high basal activity in the BDNF signaling pathway, leading to the dysregulation of BDNFmediated physiological functions underlying normal leaming and memory. This will be tested by examining BDNF signaling in genetically-modified neurons lacking NF. Although BDNF, via its cognate receptor, trkB, is known to activate multiple downstream pathways, not all of these should be affected by the loss of NF. Immunoprecipitation and proteomic analysis will be used to identify and characterize functional signaling complexes containing NF and trkB. If this hypothesis withstands the critical tests outlined in this proposal, the BDNF/trkB signaling pathway will emerge as a potential target for pharmacological or other therapies that could selectively treat the cognitive symptoms of NF1; the neurofibromas may be more effectively treated with a separate therapeutic strategy. In addition to testing this hypothesis, elucidation the components of the NF signaling complex will provide new insight into the normal function of NF and may provide additional clues to potential molecular targets for the treatment of NF1.