Investigation of how axon development is disrupted by the autism-causing Timothy syndrome mutation.

研究导致自闭症的蒂莫西综合征突变如何扰乱轴突发育。

基本信息

批准号：
10645284
负责人：
CHRISTOPHER C QUINN
金额：
$ 8.56万
依托单位：
UNIVERSITY OF WISCONSIN MILWAUKEE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10645284
关键词：
Address Affect Attention deficit hyperactivity disorder Autism Diagnosis Autophagocytosis Axon Behavior Biological Biological Process Bipolar Disorder Caenorhabditis elegans Calcium Channel Cells Complex Data Defect Development Disease Genes Genetic Genetic Screening Goals Heritability Inherited Intellectual functioning disability Investigation Light Link Major Depressive Disorder Mediating Medical Genetics Missense Mutation Modeling Molecular Mutation Nature Neurodevelopmental Disorder Organelles Pathway interactions Penetrance Process Role Schizophrenia Testing Timothy syndrome Touch sensation Variant Work autism spectrum disorder de novo mutation gain of function gene function habituation individuals with autism spectrum disorder insight loss of function loss of function mutation misfolded protein neuropsychiatric disorder novel protein degradation receptor screening ubiquitin ligase variant of unknown significance voltage

项目摘要

Autism is a highly heritable neurodevelopmental disorder that has been linked to variants in many genes. However, the biological basis of autism remains poorly understood. To gain insight into the mechanisms that cause autism, we are focusing on the Timothy syndrome mutation, a variant in the CACNA1C voltage gated calcium channel (VGCC). The Timothy syndrome mutation causes autism with high penetrance, providing a powerful avenue for investigation of the molecular mechanisms that underlie autism. Our preliminary data indicate that the Timothy syndrome mutation disrupts axon targeting in C. elegans, providing a model for understanding the role of VGCC variants in autism. In aim 1, we will investigate how VGCCs regulate axon targeting and how the Timothy syndrome mutation alters this process to affect axonal connectivity and behavior. In aim 2, we will investigate how the Timothy syndrome mutation alters autophagy and how alterations in this process affect axon targeting. In aim 3, we will determine if other missense mutations in VGCCs can alter axon targeting. These studies will provide insight into the biological basis for autism and will identify interactions between autism-linked genes that could potentially be used to predict and diagnose autism. Moreover, the CACNA1C gene has also been associated with schizophrenia, bipolar disorder, major depression and attention deficit hyperactivity disorder, suggesting that our results are likely to be more broadly applicable to other neuropsychiatric disorders.

自闭症是一种高度遗传性的神经发育障碍，与许多基因的变异。然而，自闭症的生物学基础仍然很薄弱明白了。为了深入了解导致自闭症的机制，我们重点关注蒂莫西综合征突变，CACNA1C 电压门控钙的一种变异频道（VGCC）。蒂莫西综合征突变导致高外显率的自闭症，为研究其背后的分子机制提供了强大的途径自闭症。我们的初步数据表明蒂莫西综合征突变破坏了轴突靶向秀丽隐杆线虫，为理解 VGCC 变体的作用提供模型在自闭症中。在目标 1 中，我们将研究 VGCC 如何调节轴突靶向以及如何蒂莫西综合征突变改变了这个过程，影响轴突连接和行为。在目标 2 中，我们将研究蒂莫西综合征突变如何改变自噬以及该过程的改变如何影响轴突靶向。在目标 3 中，我们将确定 VGCC 中的其他错义突变是否可以改变轴突靶向。这些研究将深入了解自闭症的生物学基础，并确定与自闭症相关的基因之间的相互作用可能被用来预测和诊断自闭症。此外，CACNA1C 基因也与精神分裂症、双相情感障碍、重度抑郁症和注意力缺陷多动症紊乱，表明我们的结果可能更广泛地适用于其他神经精神疾病。