The Role of Filamin in Periventricular Heterotopias

描述(申请人提供)：人类发育障碍 大脑皮质占癫痫病例的15%-40%，最值得注意的是 难治性的儿科癫痫。这些疾病对…有有害的影响 个人的心理和身体健康。鉴定 致病基因和它们的功能特征将提供 对癫痫的神经病理有必要的洞察，以及扩展 目前对正常皮质发育的理解。通过这样一种基因 最近的研究结果表明，肌动蛋白结合的突变 蛋白质细丝蛋白I(Fln1)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 特点是神经元的子集无法从 皮质发育过程中的脑室，与体部变薄有关 骨痂和小脑发育不全。而已知的细丝蛋白 跨多种生物调节细胞稳定性、突起和运动性 系统，它们在中枢神经系统内的潜在功能只有 最近才发现fli与PVH之间的联系。因此， 这项提案的总体目标是分析FLN1和高度 同源蛋白Fln3与神经发生、神经元迁移和 随后的分化。 具体目标1将描述细丝的时间和空间模式 蛋白质和mRNA的表达，以检验肌动蛋白结合的假设 在持续的时间段内，蛋白质定位于适当的神经元群体 皮质神经发生、迁移和轴突生长。特定目标2将 确定Fln1、Fln3和其他新的和 已知的发育基因，以检验细丝蛋白是 参与对大脑皮层发育至关重要的信号转导通路。 具体目标3将直接评估这样的功能意义 显性-否定和过度表达产生的交互作用 构造。Fln1突变小鼠也将提供一种动物模型，用于 研究神经元发育不同阶段的细丝相互作用。 应聘者已经完成了医学和研究生课程的培训。他的 住院医师培训是在神经学方面进行的，他在 神经科学研究新皮质移植范例在治疗中的作用 在两者中神经元的指定、迁移和定向分化 皮质发育和随后的靶向神经元变性。他现在正在寻找 在克里斯·沃尔什博士的指导下进行进一步培训，他的研究 兴趣集中在了解基本原理的遗传方法上 大脑皮层发育的机制。这是候选人的 打算将这些新获得的分子和遗传方法与 他之前接受的移植培训是为了追求神经学的学术生涯 和神经科学，主要是在皮质发育和 畸形，因为它们与癫痫有关。

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.