The Role of Filamin in Periventricular Heterotopias

描述（由申请方提供）：人类发育障碍 大脑皮层占癫痫病例的15- 40%， 小儿顽固性癫痫这些疾病对 个人的心理和身体健康。识别 致病基因及其功能的表征将提供 必要的洞察癫痫的神经病理学，以及扩大 目前对正常皮质发育的理解。通过这样的基因 方法，最近的研究结果表明，在肌动蛋白结合突变， 蛋白细丝蛋白I（FLN 1）与人类X-连锁疾病有关， 脑室周围异位和癫痫（PVH）。这种神经遗传性疾病是 其特征在于神经元的子集不能从 皮质生成期间的心室，与体变薄有关 胼胝体和小脑发育不全。虽然已知细丝蛋白质 调节细胞的稳定性、突起和运动性， 系统，其在中枢神经系统内的潜在功能只有 最近才发现民族解放阵线和PVH的联系因此 本提案的总体目标是分析FLN 1的作用， 同源蛋白FLN 3与神经发生、神经元迁移和 随后的分化。 具体目标1将描述细丝蛋白的时空模式， 蛋白和mRNA表达，以检验肌动蛋白结合的假设， 蛋白质定位于适当的神经元群体期间， 皮质神经发生、迁移和轴突生长。具体目标2将 鉴定FLN 1、FLN 3和其它新的和 已知的发育基因，以测试细丝蛋白质是 参与皮质发育所必需的信号转导途径。 具体目标3将直接评估这些功能的重要性， 通过产生显性阴性和过表达的相互作用 结构。FLN 1突变小鼠也将提供一种动物模型， 研究细丝蛋白在神经元发育的各个阶段的相互作用。 候选人已完成医学和研究生课程的培训。他 住院医师培训是在神经病学，他获得了博士学位， 神经科学研究新皮质移植范例的影响 神经元的特化、迁移和定向分化 皮质发育和随后的靶向神经元变性。他现在寻求 在克里斯沃尔什博士的指导下进一步培训，他的研究 兴趣集中在理解基本原理的遗传方法上 控制大脑皮层发育的机制。这是候选人的 意图将这些新获得的分子和遗传方法联合收割机 他之前接受的移植培训是为了从事神经病学的学术事业 和神经科学，主要是在皮质发育领域， 与癫痫有关的畸形。

DESCRIPTION (provided by applicant): Developmental disorders of the human cerebral cortex comprise 15-40 percent of epilepsy cases, most notably intractable pediatric seizures. These disorders have deleterious affects on both the psychological and physical well being of individuals. Identification of the causative genes and characterization of their function will provide necessary insight into the neuropathology of epilepsy as well as extend the current understanding of normal cortical development. Through such a genetic approach, recent findings have shown that mutations in the actin-binding protein filamin I (FLN1) are implicated in the human x-linked disorder, periventricular heterotopia and epilepsy (PVH). This neurogenetic disorder is characterized by the failure of subsets of neurons to migrate from the ventricle during corticogenesis, in association with thinning of the corpus callosum and cerebellar hypoplasia. While the filamin proteins are known to regulate cell stability, protrusion and motility across various biologic systems, their potential functions within the central nervous system has only just come to light with the recent association of FLNI to PVH. Thus, the overall goal of this proposal is to analyze the roles of FLN1 and a highly homologous protein, FLN3, in relation to neurogenesis, neuronal migration, and subsequent differentiation. Specific Aim 1 will characterize the temporal and spatial pattern of filamin protein and mRNA expression, to test the hypothesis that the actin-binding proteins localize to appropriate neuronal populations during periods of ongoing cortical neurogenesis, migration and axonal outgrowth. Specific Aim 2 will identify protein-protein interactions between FLN1, FLN3 and other novel and known developmental genes, to test the hypothesis that filamin proteins are involved in signal transduction pathways essential to cortical development. Specific Aim 3 will directly evaluate the functional significance of such interactions through generation of dominant-negative and overexpression constructs. FLN1 mutant mice will also provide an animal model with which to study filamin interactions during the various stages of neuronal development. The candidate has completed training in both medical and graduate programs. His residency training is in Neurology, and he earned his doctoral degree in Neuroscience studying neocortical transplantation paradigms in effecting neuronal specification, migration and directed differentiation during both cortical development and following targeted neuronal degeneration. He now seeks further training under the mentorship of Dr. Chris Walsh, whose research interests center on genetic approaches toward understanding fundamental mechanisms governing development of the cerebral cortex. It is the candidate's intention to combine these newly acquired molecular and genetic approaches with his prior training in transplantation to pursue an academic career in Neurology and the Neurosciences, primarily in the field of cortical development and malformations as they pertain to epilepsy.