Pathophysiology of MECP2 Spectrum Disorders (Career Development Award Proposal)

描述(申请人提供)：MeCP2谱系障碍包括典型的Rett综合征、带有Rett综合征变体的女性、Angelman样表型、自闭症、智力低下、学习障碍、注意力障碍，以及患有Rett综合征的男性、致命的婴儿脑病、伴有震颤/运动障碍和/或癫痫的精神发育迟滞，或以双相情感障碍或精神分裂症形式的早发性精神病。MeCP2蛋白本身的改变或MeCP2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MECP2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MECP2复制是如何导致神经功能障碍的。我建议的具体目标是1)确定染色质修饰的全球模式，2)在MECP2谱系障碍的人和小鼠模型中确定特定的MECP2靶基因，3)测试针对表观遗传修饰的治疗可以改善MECP2功能障碍小鼠模型的症状的假设。我建议使用ChlP-on-Chip技术来测试这一假设，即功能丧失和错义突变以及MECP2的复制通过改变特定位点的染色质状态导致选定基因的错误表达而导致神经功能障碍，并且恢复正常的染色质状态将改善与MECP2改变的子集相关的症状。 我的长期目标是成为一名独立的内科科学家，开展一项研究计划，旨在调查自闭症谱系障碍、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向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。我的导师胡达·佐格比博士是一位国际知名的内科医生/科学家，有着丰富的培训记录。部门对我的研究生涯的支持，与科学咨询委员会的互动，以及在贝勒和其他地方的正式课程工作，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.