SNRP at Hunter College

成纤维细胞生长因子同源因子(FHFs)是细胞内神经调节剂，其作用机制尚不清楚。携带FHF基因缺失的小鼠表现出与运动相关的神经缺陷 功能，尽管动物没有表现出可检测到的组织学或免疫组织化学异常。FHFs是 据信通过确定的结合伙伴发挥作用，其中包括电压门控钠通道。 P.I.S实验室最近的发现表明，FHFs是神经元正常的内在兴奋性所必需的，而且 FHF缺陷神经元表现出异常的电压依赖性钠通道行为。进一步的数据显示，FHF是 动作电位沿运动神经轴突的最佳传导所需。根据这些发现，本申请 建议用实验来回答与FHF生理学有关的四个问题： I.FHF是否通过直接FHF-钠通道相互作用来调节神经元的兴奋性？ 不同的FHF基因和蛋白亚型在钠通道调节和 兴奋性？ FHF蛋白水平的时间调节是否有助于内在兴奋性的可塑性？ FHF蛋白水平是否影响脱髓鞘综合征的功能严重程度？ 这些实验有望更全面地确定FHFs控制生理的机制和条件。 以及中枢神经系统的病理生理学。更具体地说，这些研究将分析FHF基因 Charcot-Marie-Tooth综合征和糖尿病周围神经病变的严重程度的潜在因素，后者 这构成了一个显著的少数群体健康差距。

Fibroblast growth factor homologous factors (FHFs) are intracellular neuromodulators whose mechanisms of action are still poorly understood. Mice bearing deletions in Fhf genes display neurological deficits associated with motor function, although the animals show no detectable histological or immunohistochemical abnormalities. FHFs are believed to exert their effects through identified binding partners, which include voltage-gated sodium channels. Recent findings from the P.I.'s lab show that FHFs are required for proper intrinsic excitability of neurons, and that FHF-deficient neurons show aberrant voltage-dependent sodium channel behavior. Further data show that FHFs are required for optimal conduction of action potentials along motor axons. In light of these findings, this application proposes experiments to answer four related questions concerning FHF physiology: I. Do FHFs modulate neuronal excitability through direct FHF-sodium channel interactions? II. Are different FHF genes and protein isoforms equivalent or distinct in terms of sodium channel modulation and excitability? III. Does temporal regulation of FHF protein levels contribute to plasticity of intrinsic excitability? IV. Do FHF protein levels impact on the functional severity of demyelination syndromes? These experiments are expected to more fully define the mechanisms and conditions by which FHFs control physiology and pathophysiology of the central nervous system. More specifically, these studies will analyze FHF genes as potential contributors to severity of Charcot-Marie-Tooth syndrome and diabetic peripheral neuropathy, the latter of which constitutes a significant minority health disparity.