Mechanisms by which Exendin-4 normalizes epigenetic modifications in IUGR liver

描述（由申请人提供）：该提案描述了一个为期5年的培训计划，用于发展内分泌学的学术生涯，研究重点是表观遗传基因调控在糖尿病中的作用。候选人是宾夕法尼亚大学医学院（PENN）儿科系的助理教授和费城儿童医院（CHOP）的主治医师。该计划是Pinney博士之前关于胰腺β细胞表观遗传基因调节工作的自然延伸。她现在将专注于表观遗传和表观基因组基因调控在糖尿病发展中的作用。丽贝卡·西蒙斯医学博士Pinney博士是表观遗传学和疾病发育起源领域公认的领导者，是宾夕法尼亚大学儿科学副教授，将监督培训计划并担任Pinney博士的主要导师。该计划将由玛丽莎·巴托洛梅博士共同指导，PENN细胞和发育生物学教授，在DNA甲基化在哺乳动物发育中的基因组印记和X失活中的作用方面是一位权威。为加强培训，一个由在肝脏葡萄糖代谢、分子生物学和高通量表观基因组分析方面具有专长的杰出科学家组成的咨询委员会已被招募提供指导。CHOP和PENN的内分泌科和儿科系提供了资源，核心设施，知识专长和潜在合作的独特组合，以支持年轻的教职员工。这是一个理想的培训环境过渡到一个独立的医生，科学家。在CHOP和PENN，很大一部分K资助的初级教师继续获得RO 1资助。宫内生长迟缓（IUGR）与成人2型糖尿病（T2 DM）的发生有关。异常的子宫内环境通过永久改变易感细胞（如肝细胞）中的基因表达来影响胎儿的发育。PPARGC 1A（PGC 1 <$）是一种调节线粒体功能的转录辅激活因子，其表达在患有T2 DM的人类和IUGR大鼠中均降低。新生儿用Exendin-4（Ex-4）治疗通过恢复USF 1结合和使IUGR诱导的PGC 1 <$启动子表观遗传修饰正常化来使PGC 1 <$基因表达正常化。中心假设是描述Exendin-4通过恢复表观遗传起始物USF 1的功能使IUGR肝脏中的表观遗传修饰正常化的机制。具体目标包括：1）通过研究USF 1作为表观遗传起始因子的作用，确定Ex-4逆转IUGR肝脏中PGC 1 <$的表观遗传修饰的机制; 2）为了确定USF 1结合是否在全局上负责维持高水平的组蛋白3乙酰化和组蛋白3赖氨酸4甲基化，组蛋白标志物与调节肝葡萄糖稳态的其他肝基因的基因转录增加相关。 公共卫生相关性：据估计，2350万美国人患有糖尿病，2006年糖尿病是美国第七大死亡原因。在多项人类研究中，宫内生长迟缓与成年后糖尿病的发生有关。确定导致2型糖尿病发展的潜在分子机制的研究以及旨在预防2型糖尿病发展的干预措施将减少这一重大公共卫生负担的影响。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in endocrinology with a research focus on the role of epigenetic gene regulation in diabetes. The candidate is an Assistant Professor in the Department of Pediatrics at the University of Pennsylvania School of Medicine (PENN) and an attending physician at The Children's Hospital of Philadelphia (CHOP). This program is a natural extension of Dr. Pinney's previous work on epigenetic gene regulation in the pancreatic beta cell. She will now focus on the role of epigenetic and epigenomic gene regulation in the liver in the development of diabetes. Rebecca Simmons, M.D., a recognized leader in the field of epigenetics and developmental origins of disease, is an Associate Professor of Pediatrics at PENN and will supervise the training program and serve as Dr. Pinney's primary mentor. The program will be co-mentored by Marisa Bartolomei, Ph.D., Professor of Cell and Developmental Biology at PENN, an established authority in the role of DNA methylation in genomic imprinting and X inactivation in mammalian development. To enhance training, an advisory committee consisting of distinguished scientists with expertise in hepatic glucose metabolism, molecular biology and high- throughput epigenomic analyses have been enlisted to provide guidance. The Division of Endocrinology and the Department of Pediatrics at CHOP and PENN provide a unique combination of resources, core facilities, intellectual expertise and potential collaborations to support a young faculty member. This is an ideal training environment to transition to an independent physician-scientist. A large percentage of K-funded junior faculty at CHOP and PENN go on to receive RO1 funding. Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes (T2DM) in adults. The abnormal intrauterine environment affects the development of the fetus by permanently modifying gene expression in susceptible cells like the hepatocyte. Expression of PPARGC1A (PGC1¿), a transcriptional coactivator that regulates mitochondrial function, is decreased in both humans with T2DM and IUGR rats. Neonatal treatment with Exendin-4 (Ex-4) normalizes PGC1¿ gene expression by restoring USF1 binding and normalizing the IUGR induced epigenetic modifications at the PGC1 ¿ promoter. The central hypothesis is to describe the mechanism by which Exendin-4 normalizes the epigenetic modifications in IUGR liver by restoring the function of the epigenetic initiator USF1. The specific aims include: 1) To determine the mechanism by which Ex-4 reverses epigenetic modifications of PGC1¿ in IUGR liver by investigating the role of USF1 as epigenetic initiator; 2) To determine if USF1 binding is globally responsible for maintaining high levels of histone 3 acetylation and histone 3 lysine 4 methylation, histone marks associated with increased gene transcription at additional hepatic genes critical for regulating hepatic glucose homeostasis. PUBLIC HEALTH RELEVANCE: 23.5 million Americans are estimated to have diabetes and in 2006 diabetes was the 7th leading cause of death in the United States. Intrauterine growth retardation has been linked to the later development of diabetes in adulthood in multiple studies in humans. Studies to determine the underlying molecular mechanisms that lead to the development of type 2 diabetes and interventions aimed and preventing the development of type 2 diabetes will reduce the impact of this major public health burden.