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.

项目摘要/摘要