Exploring the role of the protocadherin CELSR3 in Tourette syndrome

探索原钙粘蛋白 CELSR3 在抽动秽语综合征中的作用

• 批准号: 10532254
• 负责人: Marco Bortolato
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532254
• 关键词: 20 year old; Address; Adolescent; Adult; Adverse event; Affect; Age; Area; Autopsy; Behavior; Behavioral; Benchmarking; Biological Process; Birth; Blinking; Brain; Cell Communication; Cells; Characteristics; Child; Clinical Management; Corpus striatum structure; Crossbreeding; DNA Sequence Alteration; Data; Development; Disease; Disinhibition; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Etiology; Exhibits; FDA approved; Female; Fiber; Fluorescence-Activated Cell Sorting; Future; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Genetic study; Genotype; Gilles de la Tourette syndrome; Growth; Heterozygote; Human; Hyperactivity; Impairment; Individual; Interneurons; Knockout Mice; Knowledge; Measures; Modeling; Molecular; Molecular Target; Motor; Mus; Mutation; Neuroanatomy; Neurodevelopmental Disorder; Neurons; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Process; Proteins; Puberty; Recurrence; Reporter; Role; Safety; Sampling; Severities; Sex Differences; Source; Testing; Tic disorder; Time; Transgenic Mice; Wild Type Mouse; Youth; age related; behavioral impairment; behavioral outcome; behavioral response; cholinergic; de novo mutation; design; disability; early childhood; exome; experimental study; genetic pedigree; high risk; male; migration; mouse model; mutant; neural circuit; neurobehavioral; novel; pharmacologic; prepuberty; prepulse inhibition; prevent; response; risk variant; sex; side effect; stereotypy; striosome; transcriptomics

PROJECT SUMMARY / ABSTRACT Tourette syndrome (TS) is a neurodevelopmental disorder with a strong genetic component, affecting 0.5-1% of children. TS is characterized by multiple, recurring tics, which are a source of significant disability. The clinical management of TS poses considerable challenges, partially because all available pharmacotherapies are not specific to the pathogenic mechanisms, and thus have only limited efficacy and significant side effects. Understanding the genetic basis of TS is an essential step to elucidate the causes of this disorder; however, until recently, all available information was limited to rare genetic mutations sporadically associated with TS pedigrees, and thus could not be generalized to most patients. Recently, however, evidence from large genetic studies and the first gene-expression analyses of postmortem samples from TS-affected individuals has revealed that protocadherins, a superfamily of proteins regulating cell-cell interactions, play a key role in TS pathogenesis. In support of these findings, the largest whole-exome studies on de novo mutations in TS recently identified the protocadherin-encoding gene CELSR3 as one of the first high-confidence TS risk genes. This R21 proposal seeks to leverage these new discoveries and explore the mechanisms whereby CELSR3 deficiency predisposes to TS, using transgenic mouse models harboring a mutation of this gene. In preliminary studies, we found that juvenile peripubertal male and female CELSR3 heterozygous mice exhibit TS-like phenotypes, including tic-like stereotypies and sensorimotor gating deficits, in comparison with their wild-type littermates. Furthermore, previous experiments showed that CELSR3 has a critical role in interneuron migration and the organization of dopaminergic projections. Based on this background, we hypothesize that partial CELSR3 deficiency leads to TS-related neurobehavioral deficits by impairing the histoarchitectural and molecular organization of the striatum. To test this hypothesis, the two aims of this application will respectively: 1) chart the trajectory of the behavioral impairments of CELSR3 heterozygous mice; and 2) determine the histoarchitectural and transcriptomic alterations of the striatum of these mutants. The proposed exploratory studies will be the first to elucidate the role of protocadherins in TS ontogeny and validate the first model of TS based on a high-risk vulnerability gene. These results are likely to lead to the identification of novel pathogenic processes and specific molecular pathways involved in TS etiology. Our results will lead to future larger studies aimed at the analysis of early neurodevelopmental causes of TS and the design of novel specific pharmacotherapies with better efficacy, tolerability, and safety profiles.

项目概要/摘要 抽动秽语综合征 (TS) 是一种具有很强遗传因素的神经发育障碍，影响 0.5-1% 儿童。 TS 的特点是多次、反复出现抽动，这是造成严重残疾的一个原因。这 TS 的临床管理提出了相当大的挑战，部分原因是所有可用的药物疗法 其致病机制不具有特异性，因此疗效有限且副作用显着。 了解 TS 的遗传基础是阐明这种疾病病因的重要一步；然而， 直到最近，所有可用信息都仅限于与 TS 零星相关的罕见基因突变 谱系，因此不能推广到大多数患者。然而，最近来自大量遗传的证据 研究和首次对受 TS 影响的个体尸检样本进行基因表达分析 揭示了原钙粘蛋白（调节细胞间相互作用的蛋白质超家族）在 TS 中发挥关键作用 发病。为了支持这些发现，针对 TS 新生突变的最大全外显子组研究 最近确定原钙粘蛋白编码基因 CELSR3 是首批高可信度 TS 风险基因之一。 该 R21 提案旨在利用这些新发现并探索 CELSR3 的机制 使用携带该基因突变的转基因小鼠模型，缺乏该基因会导致 TS。 在初步研究中，我们发现青春期前后的雄性和雌性 CELSR3 杂合小鼠表现出 与 TS 样表型相比，包括抽动样刻板印象和感觉运动门控缺陷 野生型同窝小鼠。此外，之前的实验表明CELSR3在中间神经元中具有关键作用 迁移和多巴胺能投射的组织。基于这样的背景，我们假设 部分 CELSR3 缺陷通过损害组织结构和神经功能，导致 TS 相关的神经行为缺陷。 纹状体的分子组织。为了检验这个假设，该应用程序的两个目标将分别： 1）绘制CELSR3杂合子小鼠行为障碍的轨迹； 2) 确定 这些突变体纹状体的组织结构和转录组学改变。 拟议的探索性研究将首次阐明原钙粘蛋白在 TS 个体发育和 验证第一个基于高风险漏洞基因的 TS 模型。这些结果很可能导致 鉴定 TS 病因学中涉及的新致病过程和特定分子途径。我们的 结果将导致未来更大规模的研究，旨在分析 TS 的早期神经发育原因和 设计具有更好功效、耐受性和安全性的新型特异性药物疗法。