Epigenomic Regulation in Pancreatic Cell Growth

胰腺细胞生长的表观基因组调控

• 批准号: 10327723
• 负责人: Gwen Lomberk
• 金额: $ 47.41万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-25 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327723
• 关键词: Abnormal Cell; Affect; Aging; Animals; Basic Science; Biochemical; Biological; Cell Cycle; Cells; ChIP-seq; Chromatin; Clinical Trials; Complex; Cystic Lesion; DNA Methylation; DNA Sequence Alteration; Data; Data Reporting; Development; Diabetes Mellitus; Digestive System Disorders; Disease; Enhancers; Epigenetic Process; Evaluation; Event; Exocrine pancreas; Functional disorder; Funding; Gastroenterology; Gene Expression; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genomics; Gland; Goals; Grant; Growth; Health; Histone H3; Histone-Lysine N-Methyltransferase; Histones; Homeostasis; Human; Inherited; Investigation; KRAS oncogenesis; KRAS2 gene; KRASG12D; Knowledge; Link; Lysine; Malignant neoplasm of pancreas; Mediating; Medical Research; Medicine; Methodology; Methylation; Methyltransferase; Mission; Modeling; Modernization; Molecular; Mus; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nuclear; Oncogenes; Organ; Pain; Pancreas; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Physiological; Physiology; Prevention Protocols; Process; Public Health; Quality of life; Regulation; Request for Proposals; Signal Transduction; Source; Techniques; Testing; Tissues; Transcriptional Regulation; Triad Acrylic Resin; Ursidae Family; Whole Organism; Work; acute pancreatitis; base; cell growth; cell growth regulation; chronic pancreatitis; collaborative environment; design; epigenetic regulation; epigenomics; event cycle; experimental study; histone methylation; improved; in vivo; malformation; mortality; novel; novel strategies; pancreas development; paralogous gene; prevent; promoter; public health relevance; repaired; senescence; transcriptome sequencing; tumor

This proposal requests the renewal of our major source of long-standing funding for investigating transcription, chromatin, and epigenetics in pathophysiological mechanisms underlying pancreatic diseases. Our studies will directly extend our knowledge on common diseases, such as chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC), both painful and incurable disorders of the exocrine pancreas for which effective prevention protocols and treatments remain to be fully developed. Our OVERALL OBJECTIVE is to investigate how epigenomic regulators work as nuclear effectors of common mutations associated with human pancreatic diseases. Although we believe that our concepts and methodologies can be applied to any “mutation-epigenetic-disease triad”, we will focus on understanding histone-based pathways as effectors of KRAS in established genetically-engineered mouse and human patient-derived models of pancreatic diseases. Notably, while similar to genetic alterations epigenetic changes are inheritable, they can be reversible by pharmacological treatment. Our PRELIMINARY DATA report the discovery of a key role for the Histone H3 Lysine 9 (H3K9) methylation pathway and its associated methyltransferase, EHMT2, as an epigenetic regulator of oncogenic KRAS. EHMT2 together with its paralog EHMT1 are the main histone lysine methyltransferases responsible for catalyzing histone H3K9 dimethylation. However, no information is known regarding the function of EHMT1 and EHMT2, either separately or as a complex, in relationship to pancreas physiology or pancreatic diseases. We will test a combined, mechanistic and translational CENTRAL HYPOTHESIS, namely that the EHMT1/EHMT2 complex works as an epigenetic effector of KRAS during ADM and PanIN formation as well as their progression by pancreatitis. Our SPECIFIC AIMS are: 1. To determine mechanisms by which inactivation of the EHMT1/2 complex antagonizes KRASG12D-mediated ADM and PanIN formation alone and in pancreatitis; 2. To evaluate biochemical mechanisms by which KRAS signaling in pancreatic cells regulates the enzymatic activity of the EHMT1/2 complex; and 3. To discover epigenetic mechanisms by which the EHMT1/2 complex mediates the effects of KRAS. We will use an extensive battery of cellular, molecular and whole organism experiments, executed in a highly collaborative environment with state-of-the-art techniques. By focusing on better understanding epigenomic pathways that serve as effectors downstream of common mutations in the pancreas, our design seeks to maximize the yield of rapidly translatable mechanistic knowledge. Discoveries from this proposal will have a valuable positive impact because the application of concepts, techniques, and drugs from the field of epigenomics is anticipated to provide new opportunities for the management of patients affected by pancreatic diseases, thereby bearing significant biomedical relevance.

该提案要求更新我们用于调查转录的长期资金主要来源， 染色质和表观遗传学在胰腺疾病病理生理机制中的作用。我们的研究将 直接拓展我们对慢性胰腺炎、胰导管等常见疾病的了解 腺癌（PDAC），一种痛苦且无法治愈的外分泌胰腺疾病，有效治疗 预防方案和治疗方法仍有待充分制定。我们的总体目标是 研究表观基因组调节因子如何作为与人类相关的常见突变的核效应器 胰腺疾病。尽管我们相信我们的概念和方法可以应用于任何 “突变-表观遗传-疾病三联体”，我们将重点了解基于组蛋白的途径作为 KRAS 用于建立基因工程小鼠和人类患者来源的胰腺疾病模型。 值得注意的是，虽然与遗传改变类似，表观遗传变化是可遗传的，但它们可以通过以下方式逆转： 药物治疗。我们的初步数据报告发现了组蛋白 H3 的关键作用 赖氨酸 9 (H3K9) 甲基化途径及其相关甲基转移酶 EHMT2 作为表观遗传调节剂 致癌KRAS。 EHMT2 及其旁系同源物 EHMT1 是主要的组蛋白赖氨酸甲基转移酶 负责催化组蛋白 H3K9 二甲基化。但目前尚无关于该项目的任何信息 EHMT1 和 EHMT2 的功能，无论是单独的还是作为复合物，与胰腺生理学或 胰腺疾病。我们将测试一个组合的、机械的和转化的中心假设，即 EHMT1/EHMT2 复合物在 ADM 和 PanIN 形成过程中充当 KRAS 的表观遗传效应子 以及胰腺炎的进展。我们的具体目标是： 1. 确定机制 EHMT1/2 复合物的失活单独拮抗 KRASG12D 介导的 ADM 和 PanIN 形成 胰腺炎; 2. 评估胰腺细胞中KRAS信号调节的生化机制 EHMT1/2复合物的酶活性； 3. 发现表观遗传机制 EHMT1/2 复合物介导 KRAS 的作用。我们将使用大量的细胞、分子和 全有机体实验，在高度协作的环境中采用最先进的技术进行。 通过专注于更好地理解作为常见下游效应器的表观基因组通路 胰腺中的突变，我们的设计旨在最大限度地提高快速翻译机制的产量 知识。该提案的发现将产生宝贵的积极影响，因为应用 表观基因组学领域的概念、技术和药物预计将为 受胰腺疾病影响的患者的管理，因此具有重要的生物医学相关性。