Mouse Models of the Neuropathology of Tuberous Sclerosis Complex

结节性硬化症神经病理学小鼠模型

基本信息

批准号：
8115067
负责人：
MICHAEL J GAMBELLO
金额：
$ 25.32万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2007-09-30 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8115067
关键词：
Adult Affect Age-Months Apoptosis Astrocytes Autistic Disorder Behavioral Brain Brain Pathology Bromodeoxyuridine Cells Characteristics Collection Complex Defect Development Developmental Disabilities Disease Embryo Engineering Epilepsy Ethical Issues Fetal Tissues Foundations Functional disorder Future Genes Genetic Giant Cells Goals Hereditary Disease Hippocampus (Brain)Histology Human Immunohistochemistry Impairment Individual Knock-out Knockout Mice Knowledge Laboratories Lead Learning Lesion Modeling Morbidity - disease rate Morphology Mus Mutation Neuroglia Neurons Nodule Pathogenesis Pathology Patients Phenotype Predisposition Proteins Radial Research Project Grants Role Seizures Stem cells Subependymal System TSC1 gene TSC2 gene Testing Therapeutic Agents Therapeutic Intervention Transgenic Organisms Tuberous sclerosis protein complex Tumor Suppressor Proteins base developmental disease human FRAP1 protein human TSC1 protein human TSC2 protein in vivo insight loss of function migration mortality mouse model neurodevelopment neuropathology novel preclinical study recombinase tumor

项目摘要

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is an autosomal dominant tumor predisposition disorder affecting approximately 1/6000 individuals. Patients have mutations in either the TSC1 or TSC2 gene, encoding the proteins hamartin and tuberin, and have similar, but not identical, phenotypes. Substantial morbidity and mortality are caused by brain lesions such as tubers, subependymal nodules, and other neuronal heterotopias. These lesions are associated with seizures, autism, and other developmental disabilities. Remarkably, little is known about the pathogenesis of these lesions or how they lead to developmental disabilities. The overall goal of this project is to model, identify and study the neurodevelopmental defects that lead to the brain lesions of TSC. We have engineered a novel mouse model of the neuropathology of TSC by selectively deleting the Tsc2 gene in radial glial progenitor cells of the developing brain. These mice die from seizures between 3 weeks and a month of age and have enlarged brains, neuronal migration defects composed of giant cells, and increased numbers of astrocytes. These brain lesions are very similar to those described in humans with TSC and provide a novel model in which to study the in vivo neurodevelopmental aspects of TSC. The specific aims are: 1) to investigate how loss of function of Tsc2 in radial glia affects proliferation, differentiation and apoptosis in the developing and adult brain; 2) to understand the in vivo effects of loss of tuberin on neuronal morphology and migration; and, 3) to identify separate functions of the Tsc1 and Tsc2 genes in vivo by generating a similar Tsc1 based model and comparing its brain phenotype to the Tsc2 model. These studies will expand the understanding of tuberin and hamartin's role in the developing brain in TSC neuropathology, and in other TSC-associated diseases such as autism and epilepsy. Knowledge of independent in vivo functions of each gene may lead to targeted therapeutic interventions for patients with disease due to TSC1 mutations versus TSC2 mutations. The goal of this research project is to use mouse genetics to understand the developmental abnormalities that lead to the brain lesions of the genetic disease tuberous sclerosis complex. Well characterized models will establish a foundation for the testing of future targeted therapies and establish developmental neurobiologic differences between subsets of patients with TSC.

描述（由申请人提供）：结节性硬化症（TSC）是一种常染色体显性肿瘤易感性疾病，影响约 1/6000 的个体。患者的 TSC1 或 TSC2 基因（编码错构蛋白和马铃薯蛋白）存在突变，并且具有相似但不相同的表型。大量的发病率和死亡率是由脑部病变引起的，例如结节、室管膜下结节和其他神经元异位。这些病变与癫痫、自闭症和其他发育障碍有关。值得注意的是，人们对这些病变的发病机制或它们如何导致发育障碍知之甚少。该项目的总体目标是建模、识别和研究导致 TSC 脑损伤的神经发育缺陷。我们通过选择性删除发育中大脑的放射状胶质祖细胞中的 Tsc2 基因，设计了一种新的 TSC 神经病理学小鼠模型。这些小鼠在三周至一个月大时死于癫痫发作，并且大脑增大、由巨细胞组成的神经元迁移缺陷以及星形胶质细胞数量增加。这些脑部病变与 TSC 人类中描述的脑部病变非常相似，并提供了研究 TSC 体内神经发育方面的新模型。具体目标是：1）研究放射状胶质细胞中Tsc2功能的丧失如何影响发育中和成年大脑的增殖、分化和凋亡； 2）了解马铃薯蛋白损失对神经元形态和迁移的体内影响； 3) 通过生成类似的基于 Tsc1 的模型并将其大脑表型与 Tsc2 模型进行比较，识别 Tsc1 和 Tsc2 基因在体内的不同功能。这些研究将扩大人们对马铃薯蛋白和错构蛋白在 TSC 神经病理学以及其他 TSC 相关疾病（如自闭症和癫痫）中大脑发育中的作用的理解。了解每个基因的独立体内功能可能有助于对 TSC1 突变与 TSC2 突变引起的疾病患者进行有针对性的治疗干预。该研究项目的目标是利用小鼠遗传学来了解导致遗传性疾病结节性硬化症脑部病变的发育异常。良好表征的模型将为测试未来的靶向治疗奠定基础，并确定 TSC 患者亚群之间的发育神经生物学差异。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic activation of mTORC1 signaling worsens neurocognitive outcome after traumatic brain injury.

mTORC1 信号传导的基因激活会使创伤性脑损伤后的神经认知结果恶化。

DOI：
10.1089/neu.2014.3469
发表时间：
2015-01-13
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
Natalia S Rozas;J. Redell;Julia L. Hill;James Mckenna;A. Moore;M. Gambello;P. Dash
通讯作者：
P. Dash

Comparative analysis of Tsc1 and Tsc2 single and double radial glial cell mutants.

Tsc1 和 Tsc2 单、双放射状胶质细胞突变体的比较分析。

DOI：
发表时间：
2013-11
期刊：
影响因子：
0
作者：
Mietzsch, Ulrike;McKenna 3rd, James;Reith, R Michelle;Way, Sharon W;Gambello, Michael J
通讯作者：
Gambello, Michael J

Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse.

放射状胶质细胞中 Tsc2 的缺失模拟了小鼠结节性硬化症的脑病理学。

DOI：
发表时间：
2009-04-01
期刊：
影响因子：
3.5
作者：
Way, Sharon W;McKenna 3rd, James;Mietzsch, Ulrike;Reith, R Michelle;Wu, Henry Cheng;Gambello, Michael J
通讯作者：
Gambello, Michael J