The Role of TSC Genes During Brain Development

TSC 基因在大脑发育过程中的作用

基本信息

批准号：
8075009
负责人：
KEVIN C ESS
金额：
$ 16.56万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8075009
关键词：
Astrocytes Autistic Disorder Award Biological Assay Brain Brain Neoplasms Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Proliferation Cell division Cells Communities Cortical Malformation Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cyclins Defect Development Developmental Delay Disorders Embryo Epilepsy Extramural Activities Fibroblasts Funding Future G1 Phase Generations Genes Genetic Giant Cells Goals Hereditary Disease In Vitro Individual Injection of therapeutic agent International Knockout Mice Label Laboratories Length Link Measures Mediating Mentors Mus Mutation Neuroglia Neuronal Differentiation Neurons Neurosciences Research Nuclear Oligodendroglia Patients Phosphorylation Physicians Play Population Positioning Attribute Process Production Proliferating Relative (related person)Reporting Research Personnel Role S Phase Scientist Specific qualifier value Staging Stem cells Structure System TSC1 gene TSC2 gene Testing Therapeutic Time Tracer Tuberous sclerosis protein complex United States National Institutes of Health Universities Work brain malformation developmental neurobiology in vivo migration nerve stem cell programs

项目摘要

DESCRIPTION (PROVIDED BY APPLICANT): The goals of this proposal are to 1) define mechanisms used by the TSC genes to control the generation of neurons and then glia from neural progenitor cells and 2) determine how defects in these processes result in cortical malformations in Tuberous Sclerosis Complex (TSC). TSC is caused by mutation of either the TSC1 or TSC2 genes and is the most common genetic cause of epilepsy and autism. These features are very likely due to cortical brain malformations (tubers) that are found in almost all patients. Previous work has demonstrated severe laminar disruptions within tubers with abnormal glia, dysmorphic neurons, and "giant" cells expressing neuronal as well as glia markers. These findings suggest that the TSC genes play a critical role during the generation of specific neuronal populations as well as the switch from neuronal to glia production by neural progenitor cells. Mechanisms that normally control this process are not well understood but appear linked to cell cycle exit and the length of G1. Proliferation, total cell cycle length, and G1 duration are mediated by cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors such as p27kip1 (p27). Notably, while Tsc1 or Tsc2-deficient fibroblasts have decreased levels and activity of p27, similar alterations in Tsc1 or Tsc2-deficient neural progenitor cells have not been reported. Our Specific Aims are: 1) Determine the role of the Tsd gene on the timing of neuronal and glia production from neural progenitor cells, 2) determine G1 duration and proliferation in 7sc1-deficient neural progenitor cells, and 3) determine p27 expression, subcellular localization, and function in 7sc7-deficient neural progenitor cells. We will achieve these aims by studying 7sc1-deficient neural progenitor cells both in vivo and in vitro. The ability of these neural progenitor cells to differentiate will be determined using lineage specific markers. In addition, we will use S phase tracers to measure cell cycle length, G1 duration, and the proportion of cells that are actively proliferating in mice with Tsc1-deficient neural progenitor cells. Finally, p27 expression, subcellular localization, and function will be determined. The candidate will utilize this K08 Award to gain expertise in developmental neurobiology though interactions with his mentor, the Neuroscience research community at Vanderbilt University, and active involvement with national and international leaders in Developmental Neurobiology. Overall, this award should position him to become an independent physician-scientist who will successfully compete for future extramural NIH funding. Relevance: Tuberous Sclerosis Complex (TSC) is a genetic disease whose manifestations include seizure disorders, brain tumors, autism and developmental delay. This proposal seeks to understand the role of abnormal neural progenitor cells to TSC. These findings will likely have broad therapeutic implications for individuals with TSC as well as non-TSC patients with seizure disorders and autism.

描述（由申请人提供）：该提案的目标是1）定义TSC基因控制神经元的产生的机制，然后定义来自神经祖细胞的神经胶质，然后确定这些过程中的缺陷如何导致结节性硬化症复合物（TSC）的皮质畸形。 TSC是由TSC1或TSC2基因的突变引起的，是癫痫和自闭症的最常见遗传原因。这些特征很可能是由于几乎所有患者发现的皮质脑畸形（块茎）。先前的工作表明，具有异常的神经胶质，畸形神经元和表达神经元标记的“巨型神经元和“巨型”细胞的块茎中，严重的层流中断。这些发现表明，TSC基因在特定神经元群体的产生以及神经祖细胞从神经元到神经胶质细胞的转换中起着至关重要的作用。通常控制此过程的机制尚不清楚，但似乎与细胞周期退出和G1的长度有关。细胞周期蛋白，细胞周期蛋白依赖性激酶（CDK）和CDK抑制剂（如P27KIP1（P27））介导增殖，总细胞周期长度和G1持续时间。值得注意的是，尽管TSC1或TSC2缺陷型成纤维细胞的水平和活性降低了P27，但尚未报道TSC1或TSC2缺陷型神经祖细胞的类似改变。我们的具体目的是：1）确定TSD基因在神经祖细胞中神经元和神经胶质产生时间的作用，2）确定7SC1缺陷型神经祖细胞中G1持续时间和增殖的持续时间和增殖，以及3）确定P27的P27表达，亚细胞表达，亚细胞定位，并在7SC7缺失的神经外生细胞中起作用。我们将通过研究体内和体外研究7SC1缺陷型神经祖细胞来实现这些目标。这些神经祖细胞分化的能力将使用谱系特定标记确定。此外，我们将使用S相示踪剂来测量细胞周期的长度，G1持续时间以及在具有TSC1缺陷型神经祖细胞的小鼠中积极增殖的细胞的比例。最后，将确定p27表达，亚细胞定位和功能。候选人将利用这一K08奖，以与他的导师，范德比尔特大学的神经科学研究界进行互动，并积极参与发展中的发展神经生物学领导者。总体而言，该奖项应该使他成为一名独立的医师科学家，他将成功竞争未来的校外NIH资金。相关性：结节性硬化症复合物（TSC）是一种遗传疾病，其表现包括癫痫发作，脑肿瘤，自闭症和发育延迟。该提案试图了解异常的神经祖细胞对TSC的作用。这些发现可能对TSC的患者以及癫痫发作和自闭症患者具有广泛的治疗意义。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells.

DOI：
10.1371/journal.pone.0124649
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Grier MD;Carson RP;Lagrange AH
通讯作者：
Lagrange AH

Tuberous sclerosis complex: a brave new world?

DOI：
10.1097/wco.0b013e32832c4ff5
发表时间：
2010-04-01
期刊：
CURRENT OPINION IN NEUROLOGY
影响因子：
4.8
作者：
Ess, Kevin C.
通讯作者：
Ess, Kevin C.

Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin.

DOI：
10.1016/j.nbd.2011.08.024
发表时间：
2012-01
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
Carson, Robert P.;Van Nielen, Dominic L.;Winzenburger, Peggy A.;Ess, Kevin C.
通讯作者：
Ess, Kevin C.

Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences.