Pathophysiology of MECP2 Spectrum Disorders (Career Development Award Proposal)

MECP2 谱系疾病的病理生理学（职业发展奖提案）

基本信息

批准号：
7675939
负责人：
MELISSA Beth RAMOCKI
金额：
$ 17.04万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7675939
关键词：
Advisory Committees Affect Animals Antibodies Anxiety Attention Autistic Disorder Biological Models Bipolar Disorder Breathing Candidate Disease Gene Cell Line Characteristics Child Chromatin Chromatin Structure Complement Development Diagnostic Disease Encephalopathies Environment Epigenetic Process Epilepsy Family Female Functional disorder Future Gene Activation Gene Duplication Gene Mutation Gene Targeting Genes Genome Goals Hand Histone Deacetylase Histone H3 Histones Human Hypothalamic structure K-Series Research Career Programs Label Learning Learning Disabilities Link Lysine Maintenance Medicine Mental Retardation Mentors Methyl-CpG-Binding Protein 2 Methylation Microcephaly Missense Mutation Modeling Modification Molecular Motor Motor Activity Movement Disorders Mus Mutation Neurodevelopmental Disorder Neurologic Neurologic Dysfunctions Neurons Pathology Patients Pattern Phenotype Physicians Psychotic Disorders RNA Splicing Regulation Research Research Personnel Rett Syndrome Role Sampling Schizophrenia Scientist Secondary to Seizures Social Interaction Sodium Butyrate Speech Symptoms Syndrome Technology Testing Therapeutic Tissues Training Tremor Variant Weight base career chromatin immunoprecipitation chromatin modification cohort college design disease phenotype dosage early onset gain of function gene repression histone modification human male improved infancy loss of function lymphoblast male mouse model nervous system disorder postnatal prognostic programs promoter research study response restoration skills stereotypy success transcription factor

项目摘要

DESCRIPTION (provided by applicant): MECP2 spectrum disorders include classic Rett syndrome, females with Rett syndrome variants, Angelman-like phenotypes, autism, mental retardation, learning disabilities, attention disorders, as well as males with Rett syndrome, fatal infantile encephalopathy, mental retardation with tremors/movement disorders and/or seizures, or early onset psychosis in the form of bipolar disorder or schizophrenia. The mechanism by which alterations in the MeCP2 protein itself, or the dosage of MeCP2 protein, result in the various disease phenotypes is unclear. My proposal seeks to understand these mechanisms so that rational treatments can be developed to help children with MECP2 spectrum disorders. My goal is to determine how loss of function and missense mutations, as well as duplication of MECP2, cause neurological dysfunction. The specific aims of my proposal are 1) to identify global patterns of chromatin modification and 2) to identify specific MECP2 target genes in human and mouse models of MECP2 spectrum disorders and 3) to test the hypothesis that therapy targeted to epigenetic modifications improves symptoms in mouse models of MECP2 dysfunction. I propose to use ChlP-on-chip technology to test the hypothesis that loss of function and missense mutations, as well as duplication of MECP2, cause neurological dysfunction by altering chromatin states at specific loci resulting in the misregulated expression of select genes, and that restoration of the normal chromatin state will improve symptoms associated with a subset of MECP2 alterations. My long term goal is to become an independent physician scientist with a research program designed to investigate the molecular basis of autistic spectrum disorders, mental retardation, and developmental epilepsy syndromes and ultimately help clinicians provide accurate diagnostic, prognostic, and therapeutic information to patients and their families. Baylor College of Medicine provides the perfect environment for my success. My mentor, Dr. Huda Zoghbi, is an internationally known physician/scientist with a tremendous training record. Departmental support of my research career, interaction with a scientific advisory committee, and formal coursework at Baylor and elsewhere will also help me to achieve my goals.

描述（由申请人提供）：MECP2谱系障碍包括经典雷特综合征、女性雷特综合征变异体、Angelman样表型、自闭症、智力低下、学习障碍、注意力障碍，以及男性雷特综合征、致命性婴儿脑病、精神障碍伴有震颤/运动障碍和/或癫痫发作的迟缓，或双相情感障碍或精神分裂症形式的早发性精神病。 MeCP2 蛋白本身或 MeCP2 蛋白剂量的改变导致各种疾病表型的机制尚不清楚。我的建议旨在了解这些机制，以便开发合理的治疗方法来帮助患有 MECP2 谱系疾病的儿童。我的目标是确定功能丧失和错义突变以及 MECP2 重复如何导致神经功能障碍。我的提案的具体目标是 1) 确定染色质修饰的整体模式，2) 确定 MECP2 谱系疾病的人类和小鼠模型中的特定 MECP2 靶基因，3) 检验针对表观遗传修饰的治疗可改善症状的假设。 MECP2 功能障碍小鼠模型。我建议使用 ChlP-on-chip 技术来检验以下假设：功能丧失和错义突变以及 MECP2 的重复通过改变特定位点的染色质状态导致选定基因的表达失调，从而导致神经功能障碍。恢复正常染色质状态将改善与部分 MECP2 改变相关的症状。我的长期目标是成为一名独立的医师科学家，其研究项目旨在研究自闭症谱系障碍、精神发育迟滞和发育性癫痫综合征的分子基础，并最终帮助临床医生为患者及其患者提供准确的诊断、预后和治疗信息。家庭。贝勒医学院为我的成功提供了完美的环境。我的导师 Huda Zoghbi 博士是一位国际知名的医生/科学家，拥有丰富的培训记录。部门对我的研究生涯的支持、与科学咨询委员会的互动以及贝勒和其他地方的正式课程也将帮助我实现我的目标。