The Role of Filamin in Periventricular Heterotopias

细丝蛋白在脑室周围异位中的作用

• 批准号: 6896101
• 负责人: VOLNEY L SHEEN
• 金额: $ 17.15万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-16 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896101
• 关键词: actin binding protein; cell differentiation; cell migration; cerebral cortex; developmental neurobiology; epilepsy; gene expression; gene mutation; gene targeting; laboratory mouse; neurogenesis; neuropathology; protein protein interaction; protein structure function; sex linked trait; yeast two hybrid system

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.

描述（由申请人提供）：人类发育障碍 大脑皮层占癫痫病例的 15-40%，最值得注意的是 顽固性小儿癫痫发作。这些疾病会对身体产生有害影响 个人的心理和身体健康。鉴别 致病基因及其功能的表征将提供 对癫痫的神经病理学有必要的了解，并扩展 目前对正常皮质发育的理解。通过这样的遗传 方法，最近的研究结果表明，肌动蛋白结合的突变 蛋白丝蛋白 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是 其特征是神经元子集无法从 皮质发生过程中的心室，与语体变薄相关 胼胝体和小脑发育不全。虽然已知细丝蛋白 调节各种生物制剂中的细胞稳定性、突出和运动性 系统，它们在中枢神经系统内的潜在功能仅 最近 FLNI 与 PVH 的关联才刚刚曝光。因此， 该提案的总体目标是分析 FLN1 的作用和高度 同源蛋白 FLN3 与神经发生、神经元迁移和 后续分化。 具体目标 1 将表征细丝蛋白的时间和空间模式 蛋白质和 mRNA 表达，以检验肌动蛋白结合的假设 在持续的过程中，蛋白质定位到适当的神经元群体 皮质神经发生、迁移和轴突生长。具体目标 2 将 鉴定 FLN1、FLN3 和其他新的和 已知的发育基因，以检验细丝蛋白是 参与皮质发育必需的信号转导途径。 具体目标3将直接评估此类的功能意义 通过显性失活和过度表达的产生相互作用 构造。 FLN1突变小鼠还将提供一种动物模型 研究神经元发育各个阶段的细丝蛋白相互作用。 候选人已完成医学和研究生课程的培训。他的 他接受了神经病学住院医师培训，并获得了博士学位 神经科学研究新皮质移植范式的影响 神经元的规范、迁移和定向分化 皮质发育和随后的目标神经元变性。他现在寻求 在 Chris Walsh 博士的指导下进一步接受培训，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 打算将这些新获得的分子和遗传学方法与 他之前接受过移植培训，以从事神经病学的学术生涯 和神经科学，主要是在皮质发育和 与癫痫有关的畸形。

项目成果

Mutation in filamin A causes periventricular heterotopia, developmental regression, and West syndrome in males.

细丝蛋白 A 的突变会导致男性脑室周围异位、发育退化和 West 综合征。

• 发表时间: 2006-01
• 影响因子: 5.6
• 作者: Masruha, Marcelo R;Caboclo, Luis O S F;Carrete Jr, Henrique;Cendes, Iscia L;Rodrigues, Murilo G;Garzon, Eliana;Yacubian, Elza M T;Sakamoto, Americo C;Sheen, Volney;Harney, Megan;Neal, Jason;Hill, R Sean;Bodell, Adria;Walsh, Christopher;Vilan
• 通讯作者: Vilan

Cerebral developmental disorders.

大脑发育障碍。

• 发表时间: 2006-12
• 影响因子: 3.6
• 作者: Lian, Gewei;Sheen, Volney
• 通讯作者: Sheen, Volney

Cerebellar ataxia with progressive improvement.

小脑共济失调逐渐改善。

• 发表时间: 2006-04
• 作者: Tsao, Jack W;Neal, Jason;Apse, Kira;Stephan, Mark J;Dobyns, William B;Hill, Robert S;Walsh, Christopher A;Sheen, Volney L
• 通讯作者: Sheen, Volney L

Malformations of cortical development.

皮质发育畸形。

• 发表时间: 2008-05
• 作者: Pang, Trudy;Atefy, Ramin;Sheen, Volney
• 通讯作者: Sheen, Volney

Images in clinical medicine. Herpes zoster ophthalmicus followed by contralateral hemiparesis.

临床医学中的图像。

• 发表时间: 2002-04-11
• 作者: Nogueira, Raul G;Sheen, Volney L
• 通讯作者: Sheen, Volney L