Epigenomic Regulation in Pancreatic Cell Growth

胰腺细胞生长的表观基因组调控

• 批准号: 10321765
• 负责人: Gwen Lomberk
• 金额: $ 7.28万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321765
• 关键词: Area; Award; Basic Science; Bioinformatics; ChIP-seq; Clinical; Cystic Lesion; DNA Methylation; DNA Sequence Alteration; Data; Data Analyses; Development; Development Plans; Digestive System Disorders; Disease; Disease Progression; Doctor of Philosophy; Epigenetic Process; Evaluation; Event; Exocrine pancreas; Gene Expression; Genetic; Goals; Growth; Health; Health Sciences; Heterogeneity; Homeostasis; Hormone secretion; Hormones; Human; Interruption; Investigation; Islet Cell Tumor; Laboratories; Lead; Link; Malignant neoplasm of pancreas; Mediating; Medical Research; Mentors; Methodology; Methylation; Minority; Modification; National Institute of Diabetes and Digestive and Kidney Diseases; Pancreas; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatitis; Parents; Pathway interactions; Patients; Phenotype; Prognosis; Public Health; Quality of life; Regulation; Research; Research Design; Research Personnel; Role; Symptoms; Syndrome; Tissues; Translational Research; United States National Institutes of Health; Untranslated RNA; career development; cell growth; cell growth regulation; design; epigenetic regulation; epigenomics; experience; histone modification; improved; mortality; neoplastic; novel strategies; pancreas development; parent grant; programs; public health relevance; rare cancer; transcriptome sequencing; treatment response; tumor; tumorigenesis

PROJECT SUMMARY This objective of this Research Supplement to Promote Diversity in Health-Related Research (PA-21-071) is to provide a mentored experience in basic and translational science for Dr. Callisia N. Clarke. The purpose of the parent R01 (DK052913; Raul Urrutia, MD; contact PI; and Gwen Lomberk, PhD; PI) is to investigate the role of epigenetic regulation in pathophysiological mechanisms underlying pancreatic diseases and to understand how potentially druggable epigenomic landscapes, identified from patient-derived material, are linked to development of preneoplastic and neoplastic diseases of the pancreas. Cell growth regulation that is vital for pancreatic development and homeostasis is altered in most pancreatic disease states, including cystic lesions, IPMN, and pancreatic cancer. Research conducted in the mentors' laboratories on patient derived tissue encompasses a multi-parametric integrative analysis of ChIP-seq on multiple histone modifications, RNA-seq, and DNA methylation to define epigenomic signatures for human pancreatic ductal adenocarcinoma (PDAC) subtypes, which can predict their relative aggressiveness and survival[1]. However, little is known about the impact of epigenetic regulation on the development and progression of pancreatic neuroendocrine tumors (PNET). PNETs are rare tumors with significant heterogeneity in clinical presentation and prognosis. Functional PNET (F-PNET) are associated with hormone secretion causing a clinical syndrome, while non-functional (NF-PNET) tumors are not associated with hormone-driven symptoms. This supplemental application is designed to expand studies of the parent grant beyond PDAC and characterize modifications in gene expression mediated by noncoding RNA (ncRNA) in PNET. Our Central Hypothesis is that epigenetic mechanisms, at the level of ncRNA, lead to silencing of the functional phenotype of PNET, yielding NF-PNET. Our specific aims are: 1. To determine the distinct epigenomic signatures that exist between F-PNET and NF-PNET using ncRNA sequencing analysis and 2. To evaluate the impact of ncRNA signatures on NF-PNET treatment response, disease progression, and patient survival. Dr. Clarke will be mentored by an outstanding team of investigators with complementary expertise in the areas of epigenomics and bioinformatics. The mentoring/career development plan will focus on research design, methodology, and data analysis. The proposed research aligns with the parent R01 study in conceptual framework and necessary expertise. Furthermore, this Research Supplement will help in our commitment to promote the growth of one of our minority researchers in health sciences. Results from this study will serve as preliminary data for a NIH K08 award. Dr. Clarke's long-term goal is to develop her independent research program in PNET tumorigenesis and to identify potentially actionable epigenetic pathways to interrupt progression of this disease.

项目概要 本研究增刊促进健康相关研究的多样性 (PA-21-071) 的目的是 为 Callisia N. Clarke 博士提供基础科学和转化科学方面的指导经验。目的 母体 R01（DK052913；Raul Urrutia，医学博士；联系人 PI；和 Gwen Lomberk，博士；PI）的作用是研究 胰腺疾病病理生理机制中的表观遗传调控并了解如何 从患者来源的材料中鉴定出的潜在可药物化的表观基因组景观与发育相关 胰腺癌前期和肿瘤性疾病。对胰腺至关重要的细胞生长调节 大多数胰腺疾病状态下的发育和稳态都会改变，包括囊性病变、IPMN 和 胰腺癌。在导师实验室对患者来源的组织进行的研究包括 对多个组蛋白修饰、RNA-seq 和 DNA 进行 ChIP-seq 的多参数综合分析 甲基化来定义人类胰腺导管腺癌（PDAC）亚型的表观基因组特征， 可以预测它们的相对攻击性和生存率[1]。然而，人们对它的影响却知之甚少 表观遗传调控胰腺神经内分泌肿瘤（PNET）的发生和进展。 PNETs 是临床表现和预后具有显着异质性的罕见肿瘤。功能性 PNET (F-PNET) 与引起临床综合征的激素分泌有关，而非功能性 (NF-PNET) 肿瘤则 与激素驱动的症状无关。该补充应用程序旨在扩展以下研究 父母授予超越 PDAC 的权利并描述非编码 RNA 介导的基因表达修饰 (ncRNA) 在 PNET 中。我们的中心假设是 ncRNA 水平的表观遗传机制导致 PNET 功能表型的沉默，产生 NF-PNET。我们的具体目标是： 1. 确定 使用 ncRNA 测序分析 F-PNET 和 NF-PNET 之间存在的不同表观基因组特征 2. 评估 ncRNA 特征对 NF-PNET 治疗反应、疾病进展和 患者生存。克拉克博士将得到一支优秀的研究人员团队的指导，他们具有互补性 表观基因组学和生物信息学领域的专业知识。指导/职业发展计划将重点关注 研究设计、方法论和数据分析。拟议的研究与父 R01 研究一致 概念框架和必要的专业知识。此外，本研究增刊将有助于我们 致力于促进我们健康科学领域少数族裔研究人员的成长。这项研究的结果 将作为 NIH K08 奖项的初步数据。克拉克博士的长期目标是发展她的独立能力 PNET 肿瘤发生的研究计划，并确定潜在可行的表观遗传途径来中断 这种疾病的进展。