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Development of a novel rodent model of hypothalamic hamartoma and epilepsy

下丘脑错构瘤和癫痫的新型啮齿动物模型的开发

基本信息

批准号：
10354125
负责人：
PETER J WEST
金额：
$ 41.94万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354125
关键词：
Affect Anatomy Animal Model Behavioral Cell Proliferation Cells Child Chromosome Mapping Clinical Communities Cre-LoxP Cytoplasmic Granules Development Down-Regulation Electrophysiology (science)Embryo Embryonic Development Epilepsy Epileptogenesis Etiology Excision Functional disorder Future G-Protein-Coupled Receptors GLI3 gene Gene Expression Genes Genetic Predisposition to Disease Genetic Recombination Goals Growth Histopathology Human Hypothalamic structure Lead Mosaicism Mus Mutation Neurons Operative Surgical Procedures Patients Pharmaceutical Preparations Pharmacological Treatment Phenotype Physiology Problem Solving Refractory Research Resected Resistance Rodent Model Role SHH gene Secondary to Seizures Signal Pathway Signaling Molecule Somatic Mutation Sonic Hedgehog Pathway Source Tamoxifen Testing Tissue Sample Tissues Up-Regulation Work cell type childhood epilepsy experimental study high risk hypothalamus hamartoma medulloblastoma mouse model mutant nerve stem cell neurogenesis novel novel therapeutic intervention novel therapeutics receptor smoothened signaling pathway sonic hedgehog receptor transcription factor

项目摘要

ABSTRACT: Hypothalamic Hamartomas (HH) are noncancerous growths of disorganized cells and are believed to result as a consequence of somatic mutations in sonic hedgehog (SHH) pathway genes during embryonic development. HH are associated with gelastic seizures (GS) that are difficult to control with existing anti-seizure drugs, and people with HH also go on to develop even more severe pharmacoresistant seizure types due to secondary epileptogenesis. Thus, there is a significant clinical need to develop new therapies to treat the debilitating pharmacoresistant seizures that result as a direct consequence of HH and/or that develop following secondary epileptogenesis. A complete absence of animal models that recapitulate the phenotypes resulting from HH is a significant reason why discovery and development of novel pharmacological treatments has been hindered. The present R21 proposal seeks to solve this problem by generating a novel mouse model of HH for use in therapy discovery. This goal will be accomplished by utilizing tamoxifen-inducible Cre-Lox recombination to independently express and test two etiologically relevant somatic mutations in SHH signaling molecules during periods of peak hypothalamic cellular proliferation and examine resultant hypothalamic anatomy, gene expression, and physiology in these mice. Since activation of SHH signaling is known to promote cell proliferation, Aim 1 will independently examine the effects of expressing SmoM2 (a constitutively activated form of the Smoothened GPCR) that will produce a cell autonomous upregulation of SHH signaling in a mosaic of affected cells in the developing hypothalamus. Aim 2 will independently examine the effects of expressing a truncated version of the SHH pathway transcription factor GLI3 (GLI3T) that has been shown in resected HH tissues. Expression of GLI3T acts as a constitutive repressor and is expected to downregulate SHH signaling. Downregulation of SHH signaling in a limited number of cells may not conflict with our hypothesis that an overall upregulation of SHH signaling is responsible for the development of HH because, as it has recently been demonstrated, a loss of SHH signaling in a mosaic of developing hypothalamic cells can cause a cell non- autonomous upregulation of SHH signaling in neighboring wild-type cells. Therefore, this R21 proposal will utilize existing mouse lines to directly test the hypothesis that development of HH and consequent seizure phenotypes can result from somatic mutations that produce either a cell autonomous or non-autonomous upregulation in SHH signaling during hypothalamic development. Thus, this work has the potential to provide the field with the first animal model of HH and sets the stage for future work to determine novel therapeutic approaches for the treatment of refractory seizures and to examine the mechanisms underlying secondary epileptogenesis.

摘要：下丘脑错构瘤（Hypothalamic hammartomas， HH）是一种由无序细胞组成的非癌性肿瘤