The Role of GPR161 in the Etiology of Neural Tube Defects

GPR161 在神经管缺陷病因学中的作用

基本信息

批准号：
10424509
负责人：
RICHARD H. FINNELL
金额：
$ 38.29万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10424509
关键词：
3-Dimensional Adult Adverse effects Affect Apoptosis Biochemical Biological Assay Biological Models CRISPR/Cas technology Candidate Disease Gene Cell Culture System Cell Line Cell Polarity Cell Proliferation Cell model Cell physiology Cells Cellular Morphology Cephalic Child Complex Congenital Abnormality Craniofacial Abnormalities Critical Pathways Cyst Cytoskeleton Data Defect Development Embryo Embryonic Development Environmental Risk Factor Etiology Failure Family Gene Expression Generations Genes Genetic Genetic Epistasis Haploidy Human Impairment In Vitro Infant Intervention Knock-in Knock-in Mouse Knock-out Knockout Mice Laboratories Lead Link Maps Measures Modeling Molecular Morphogenesis Mus Neural Crest Cell Neural Tube Closure Neural Tube Defects Neural tube Neuroepithelial Partner in relationship Patients Pattern Phenotype Predisposition Process Proteomics Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Structural Congenital Anomalies System Technology Testing Variant androgenic base cell motility cohort conditional knockout craniofacial development developmental genetics embryonic stem cell gene network genetic variant genome editing genome sequencing improved in vivo in vivo Model malformation migration mouse model nerve stem cell nestin protein novel novel therapeutic intervention polarized cell programs rare variant risk variant stem cell proliferation stem cells treatment strategy whole genome

项目摘要

ABSTRACT Neural tube defects (NTDs) are the second most common human structural birth defect. They result from the failure of neural tube closure (NTC) during neurulation. There are multiple developmentally-related signaling pathways involved as NTC processes spatially and temporally. The causes of NTDs are known to be multi- factorial, including genetic and environmental factors. Given that the genetic factors contribute significantly to the etiology of NTDs, the identification of specific gene variants and the characterization of their underlying molecular and cellular mechanisms leading to the etiology of NTDs has progressed slowly over the last several decades. We have identified novel rare variants of GPR161 using whole genome sequencing (WGS) from large human cohorts. GPR161 is a known negative regulator of the Shh signaling pathway, and Shh null mice express NTD phenotypes. The GPR161vl and null mice models suggest the involvement of other signaling pathways. The Shh, Wnt and PCP signaling pathways are involved in the neural tube patterning, neural stem cell proliferation, and neural crest cell migration via cell polarization during NTC. We will test the following specific hypothesis with in vitro and in vivo models. (1) GPR161 can regulate Wnt and PCP signaling pathways, and the novel rare gene variants of GPR161 adversely impact these signaling pathways, which dysregulate NTC. (2) GPR161 can impact cell proliferation and cell polarity via Wnt and PCP signaling, respectively, thus the NTD variants of GPR161 will increase NTD susceptibility by compromising these processes. (3) The identified human GPR161 NTD variants, alone or in combination with other PCP genes, will produce NTD phenotypes in knock in (KI) mouse models. The proposed research program will provide the novel molecular, cellular, developmental and genetic links between GPR161, Wnt and PCP signaling pathways, as they relate to morphogenetic processes involved in normal NTC. Filling this large datagap can lead us to novel therapeutic strategies for both intervention and treatment.

抽象的神经管缺陷（NTD）是第二常见的人类结构性出生缺陷。它们的结果是神经形成过程中神经管闭合（NTC）失败。有多种与发育相关的信号传导 NTC 过程涉及空间和时间的途径。 NTD 的成因已知有多种：因素，包括遗传因素和环境因素。鉴于遗传因素对 NTD 的病因学、特定基因变异的识别及其潜在特征的表征导致 NTD 病因学的分子和细胞机制在过去几年中进展缓慢几十年。我们通过全基因组测序（WGS）从大型人类群体。 GPR161 是 Shh 信号通路的已知负调节因子，Shh 缺失小鼠表达 NTD 表型。 GPR161vl 和无效小鼠模型表明其他信号通路的参与。这 Shh、Wnt 和 PCP 信号通路参与神经管模式、神经干细胞增殖、 NTC 期间通过细胞极化进行神经嵴细胞迁移。我们将测试以下具体假设体外和体内模型。 (1) GPR161可调控Wnt和PCP信号通路，是新型稀有基因 GPR161 的变体会对这些信号通路产生不利影响，从而导致 NTC 失调。 (2) GPR161可以影响细胞增殖和细胞极性分别通过 Wnt 和 PCP 信号传导，因此 GPR161 的 NTD 变体将通过损害这些过程来增加 NTD 的易感性。 (3) 已鉴定的人类 GPR161 NTD 变体，单独或与其他 PCP 基因组合，将在敲入 (KI) 小鼠模型中产生 NTD 表型。拟议的研究计划将提供新颖的分子、细胞、发育和遗传联系 GPR161、Wnt 和 PCP 信号通路之间的关系，因为它们与参与的形态发生过程有关正常NTC。填补这一巨大的数据空白可以引导我们针对干预和治疗制定新的治疗策略。治疗。