Pathophysiology of MECP2 Spectrum Disorders (Career Development Award Proposal)

描述（由申请人提供）：MECP 2谱系障碍包括经典Rett综合征、Rett综合征变异型女性、Angelman样表型、自闭症、精神发育迟滞、学习障碍、注意力障碍，以及Rett综合征男性、致死性婴儿脑病、伴有震颤/运动障碍和/或癫痫发作的精神发育迟滞或双相情感障碍或精神分裂症形式的早发性精神病。MeCP 2蛋白本身的改变或MeCP 2蛋白的剂量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MECP 2谱系障碍的儿童。 我的目标是确定功能丧失和错义突变以及MECP 2的复制如何导致神经功能障碍。我的提案的具体目的是1）鉴定染色质修饰的全局模式，2）鉴定MECP 2谱系障碍的人类和小鼠模型中的特定MECP 2靶基因，3）测试靶向表观遗传修饰的治疗改善MECP 2功能障碍的小鼠模型中的症状的假设。我建议使用ChIP芯片技术来测试的假设，即功能丧失和错义突变，以及重复的MECP 2，通过改变在特定位点的染色质状态，导致选择基因的表达失调，导致神经功能障碍，恢复正常的染色质状态将改善与MECP 2改变的子集相关的症状。 我的长期目标是成为一名独立的医生科学家，其研究项目旨在调查自闭症谱系障碍，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家属提供准确的诊断，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，以及贝勒大学和其他地方的正式课程也将帮助我实现我的目标。

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.