Microglial Contributions to MEF2C Haploinsufficiency Syndrome

小胶质细胞对 MEF2C 单倍体不足综合征的贡献

• 批准号: 10240621
• 负责人: Catherine M Bridges Adams
• 金额: $ 5.01万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 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/10240621
• 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

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单倍症综合征（MHS）是与自闭症有关的令人衰弱的神经发育障碍 频谱障碍（ASD）。社会/沟通缺陷和重复/固定行为的核心症状定义 ASD。 MHS是一种与ASD相关的综合症，其特征是ASD符号，例如贫穷的互惠社交 行为，缺乏言语和重复行为。除了ASD症状，智力残疾，癫痫发作， 在MHS患者中还观察到运动问题。 MHS遗传与突变有关 在5染色体上的MEF2C基因的两个副本之一中删除，称为MEF2C单倍宽度。 目前尚无FDA批准的MHS治疗方法，并且需要更多了解 该综合征背后的机制。已经开发了研究该综合征的小鼠模型，其中一个 MEF2C基因的副本在外显子2（MEF2C +/-小鼠）中具有删除，称为MEF2C杂合性。这些老鼠 表现出使人联想到MHS的行为，包括社会互动和沟通不足。大多数研究 MHS专注于大脑中的神经元，而不是表达MEF2C的小胶质细胞。除了清理 已经观察到脑碎屑，小胶质细胞，大脑的常驻免疫细胞，已观察到塑造神经和突触 电路。由于小胶质细胞也表达MEF2C并在大脑中具有关键功能，因此该提案的目的 奖学金是为了调查小胶质细胞可能对MEF2C单倍不足的可能贡献 综合征相关的表型。我们假设MEF2C杂合性导致小胶质细胞的变化 生理学，导致行为表型异常。我计划通过两个目标使用鼠标模型 检查这个假设。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 基因表达。目标1在受限的MEF2C杂合的小鼠中研究这种激活的建议 种群，包括大脑中的小胶质细胞。除了确认可能的小胶质激活外，AIM 1 通过RNA序列和后续的提议研究MEF2C +/-小胶质细胞可能的功能变化 基因本体分析。特定的目标2建议MEF2C单倍症综合征与与 小胶质细胞中MEF2C的小鼠的行为。预期结果包括其中的小胶质细胞 小鼠模型的激活和小胶质功能的变化增加。如果行为定义在 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性机制。 拟议的奖学金将帮助调查人员实现她成为身体科学家的目标。 在此奖学金申请中概述了研究人员的背景和培训潜力。该提议是 独特地适合该调查员的培训需求，包括实验设计培训，技术 实验室技能，科学和道德。这项研究和培训将在医科大学进行 南卡罗来纳州的摄于协作环境和许多设施，以支持调查人员的培训。