Microglial Contributions to MEF2C Haploinsufficiency Syndrome

小胶质细胞对 MEF2C 单倍体不足综合征的贡献

基本信息

批准号：
10017058
负责人：
Catherine M Bridges Adams
金额：
$ 4.83万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017058
关键词：
Address Affect Alleles Behavior Behavioral Brain Cell Density Cell Lineage Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Child Chromosome 5 Chromosome abnormality Communication Data Development Disease Epilepsy Ethics Exhibits Exons Experimental Designs Eye FDA approved Fellowship Female Functional disorder Gene Expression Genes Genetic Goals Heritability Heterozygote Human Hyperactive behavior Immune Immune system Individual Intellectual functioning disability Investigation Knowledge Laboratories Lead Learning Link Literature Measures Medical Memory Microglia Modeling Molecular Abnormality Motor Movement Mus Mutation Neurodevelopmental Disorder Neuroimmune Neuroimmunomodulation Neurons Ontology Patients Phenotype Physicians Physiology Population Prevalence Regulation Research Research Personnel Research Training Role Scholarship Scientist Seizures Shapes Social Behavior Social Interaction South Carolina Speech Symptoms Syndrome Training Ultrasonics Universities autism spectrum disorder autistic base behavior influence behavior test behavioral phenotyping brain cell cell type collaborative environment immunoreactivity investigator training male mouse model myocyte-specific enhancer-binding factor 2 neural circuit public health relevance repetitive behavior sex skills social communication symptom cluster transcription factor transcriptome sequencing trend vocalization

项目摘要

MEF2C Haploinsufficiency Syndrome (MHS) is a debilitating neurodevelopmental disorder related to autism spectrum disorders (ASD). Core symptoms of social/communication deficits and repetitive/fixed behaviors define ASD. MHS is an ASD-related syndrome characterized by ASD symptoms, such as poor reciprocal social behavior, lack of speech, and repetitive behaviors. In addition to ASD symptoms, intellectual disability, seizures, and motor movement issues are also observed in MHS patients. MHS is genetically linked to mutations and deletions in one of the two copies of the MEF2C gene on chromosome 5, termed MEF2C haploinsufficiency. There are currently no FDA approved treatments for MHS, and there is a need for more knowledge of the mechanisms behind this syndrome. Mouse models to study this syndrome have been developed, in which one copy of the Mef2c gene has a deletion in exon 2 (Mef2C+/- mice), termed Mef2c heterozygosity. These mice exhibit behaviors reminiscent of MHS, including social interaction and communication deficits. Most studies into MHS have focused on neurons in the brain but, not microglia, which also express MEF2C. In addition to clearing brain debris, microglia, the resident immune cells of the brain, have been observed shaping neural and synaptic circuitry. Since microglia also express MEF2C and have pivotal functions in the brain, the goal of this proposed fellowship is to investigate the possible contributions that microglia could have on MEF2C Haploinsufficiency Syndrome-related phenotypes. We hypothesize that Mef2c heterozygosity leads to changes in microglial cell physiology, which results in aberrant behavioral phenotypes. I plan to use mouse models through two aims to examine this hypothesis. Specific aim 1 plans to determine the role of Mef2c in microglial activation and microglial gene expression. Aim 1 proposes to study this activation in mice that are heterozygous for Mef2c in a restricted population, which includes microglia in the brain. In addition to confirming possible microglial activation, aim 1 proposes to study possible functional changes in Mef2C+/- microglia through RNA-sequencing and subsequent gene ontology analysis. Specific aim 2 proposes to characterize MEF2C Haploinsufficiency Syndrome-related behaviors in mice heterozygous for Mef2c in microglia. Expected results include findings that microglia in these mouse models have increased activation and changes in microglial function. If behavior deficits are seen in the microglia-restricted Mef2c mice, this could explain a cell type-specific neuroimmune mechanism of MHS. This proposed fellowship would assist the investigator in achieving her goal to become a physician-scientist. The background and training potential of the investigator is outlined in this fellowship application. This proposal is uniquely suited to the training needs of this investigator, including training in experimental design, technical laboratory skills, scholarship, and ethics. This research and training will be performed at the Medical University of South Carolina, which has a collaborative environment and many facilities to support the investigator’s training.

MEF2C 单倍体不足综合症 (MHS) 是一种与自闭症相关的衰弱性神经发育障碍谱系障碍（ASD）的核心症状是社交/沟通缺陷和重复/固定行为。 MHS 是一种与 ASD 相关的综合征，其特征是 ASD 症状，例如互惠社交能力差。行为、缺乏言语和重复行为除了自闭症谱系障碍症状、智力障碍、癫痫发作、 MHS 患者中也观察到运动问题，MHS 与基因突变有关。 5 号染色体上 MEF2C 基因两个拷贝之一的缺失，称为 MEF2C 单倍体不足。目前尚无 FDA 批准的 MHS 治疗方法，需要更多的了解研究这种综合征背后的机制已经开发出来，其中一个 Mef2c 基因的副本在外显子 2 中存在缺失（Mef2C+/- 小鼠），称为 Mef2c 杂合性。大多数研究都表现出类似于 MHS 的行为，包括社交互动和沟通缺陷。 MHS 关注的是大脑中的神经元，而不是小胶质细胞，小胶质细胞除了清除之外还表达 MEF2C。脑碎片、小胶质细胞是大脑的常驻免疫细胞，已被观察到神经塑造和突触由于小胶质细胞也表达 MEF2C 并在大脑中具有关键功能，因此该提议的目标是奖学金的目的是研究小胶质细胞对 MEF2C 单倍体不足的可能贡献我们发现 Mef2c 杂合性会导致小胶质细胞的变化。生理学，这会导致异常的行为表型，我计划通过两个目的使用小鼠模型。检查这一假设。具体目标 1 计划确定 Mef2c 在小胶质细胞激活和小胶质细胞中的作用。目标 1 提议在限制性条件下研究 Mef2c 杂合小鼠的这种激活。群体，其中包括大脑中的小胶质细胞除了确认可能的小胶质细胞激活之外，目标 1 提议通过 RNA 测序和后续研究来研究 Mef2C+/- 小胶质细胞可能的功能变化基因本体分析。具体目标 2 提出描述 MEF2C 单倍体不足综合征相关的特征。小胶质细胞中 Mef2c 杂合的小鼠的行为预期结果包括这些小胶质细胞中的发现。如果在模型中观察到行为缺陷，则小鼠模型的小胶质细胞功能会增加激活和变化。小胶质细胞限制的 Mef2c 小鼠，这可以解释 MHS 的细胞类型特异性神经免疫机制。拟议的奖学金将帮助研究者实现成为一名医师科学家的目标。该奖学金申请概述了研究者的背景和培训潜力。独特地适合该研究者的培训需求，包括实验设计、技术培训这项研究和培训将在医科大学进行。南卡罗来纳州拥有协作环境和许多设施来支持调查员的培训。