The Role of TSC Genes During Brain Development

TSC 基因在大脑发育过程中的作用

• 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
• 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

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）：本提案的目标是 1) 定义 TSC 基因用于控制神经元生成以及神经祖细胞生成神经胶质细胞的机制，以及 2) 确定这些过程中的缺陷如何导致结节性硬化症 (TSC) 的皮质畸形。 TSC 是由 TSC1 或 TSC2 基因突变引起的，是癫痫和自闭症最常见的遗传原因。这些特征很可能是由于几乎所有患者都存在的皮质脑畸形（结节）造成的。先前的工作已经证明块茎内存在严重的层状破坏，其中包括异常神经胶质、畸形神经元和表达神经元和神经胶质标记物的“巨”细胞。这些发现表明，TSC 基因在特定神经元群体的生成以及神经祖细胞从神经元生成到神经胶质细胞生成的转变过程中发挥着关键作用。通常控制这一过程的机制尚不清楚，但似乎与细胞周期退出和 G1 长度有关。增殖、总细胞周期长度和 G1 持续时间由细胞周期蛋白、细胞周期蛋白依赖性激酶 (cdk) 和 cdk 抑制剂（例如 p27kip1 (p27)）介导。值得注意的是，虽然 Tsc1 或 Tsc2 缺陷的成纤维细胞 p27 的水平和活性降低，但 Tsc1 或 Tsc2 缺陷的神经祖细胞中的类似改变尚未报道。我们的具体目标是：1) 确定 Tsd 基因对神经祖细胞产生神经元和神经胶质细胞的时间的作用，2) 确定 7sc1 缺陷的神经祖细胞中的 G1 持续时间和增殖，以及 3) 确定 7sc7 缺陷的神经祖细胞中的 p27 表达、亚细胞定位和功能。我们将通过体内和体外研究 7sc1 缺陷的神经祖细胞来实现这些目标。这些神经祖细胞的分化能力将使用谱系特异性标记来确定。此外，我们将使用 S 期示踪剂来测量 Tsc1 缺陷神经祖细胞小鼠中的细胞周期长度、G1 持续时间以及活跃增殖的细胞比例。最后，将确定 p27 表达、亚细胞定位和功能。候选人将利用这个 K08 奖，通过与他的导师、范德比尔特大学神经科学研究界的互动，并积极参与发育神经生物学领域的国家和国际领导者的活动，获得发育神经生物学方面的专业知识。总体而言，该奖项将使他成为一名独立的医师科学家，并将成功竞争未来的 NIH 校外资助。相关性：结节性硬化症（TSC）是一种遗传性疾病，其表现包括癫痫症、脑肿瘤、自闭症和发育迟缓。该提案旨在了解异常神经祖细胞对 TSC 的作用。这些发现可能对 TSC 患者以及患有癫痫症和自闭症的非 TSC 患者产生广泛的治疗意义。

项目成果

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

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

• DOI: 10.1016/j.bbr.2015.05.045
• 发表时间: 2015-09-15
• 期刊: BEHAVIOURAL BRAIN RESEARCH
• 影响因子: 2.7
• 作者: Grier, Mark D.;Carson, Robert P.;Lagrange, Andre H.
• 通讯作者: Lagrange, Andre H.

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.

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.