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.

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躁郁症或精神分裂症的形式。 MECP2蛋白本身或MECP2蛋白剂量的改变的机制尚不清楚各种疾病表型。我的建议旨在理解这些机制，以便可以开发理性治疗以帮助MECP2频谱障碍儿童。我的目标是确定功能和错义突变的丧失以及MECP2的重复如何引起神经功能障碍。我的提案的具体目的是1）确定染色质修饰的全球模式和2）确定MECP2谱系疾病的人和小鼠模型中的特定MECP2靶基因，以及3）测试以表观遗传修饰的治疗可改善MECP2功能障碍小鼠模型的症状的假说。我建议使用CHLP-on-Chip技术来检验以下假设：通过改变特定基因座的染色质状态，通过改变染色质状态，导致神经功能障碍导致神经功能障碍，导致选择基因的表达错误，而正常染色质状态的恢复将改善与MECP2相关的症状相关的症状。我的长期目标是通过研究计划成为一名独立的医师科学家，旨在研究自闭症谱系障碍，智力低下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及其家人提供准确的诊断，预后和治疗信息。贝勒医学院为我的成功提供了完美的环境。我的导师Huda Zoghbi博士是一位知名的医师/科学家，拥有丰富的培训记录。我的研究职业的部门支持，与科学咨询委员会的互动以及在贝勒和其他地方的正式课程的互动也将帮助我实现自己的目标。