权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenomic Regulation in Pancreatic Cell Growth

胰腺细胞生长的表观基因组调控

基本信息

批准号：
10600724
负责人：
Gwen Lomberk
金额：
$ 3.64万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-25 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10600724
关键词：
Abnormal Cell Acceleration 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 Laboratory Organism 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 Whole Organism Work acute pancreatitis cell growth cell growth regulation chronic pancreatitis collaborative environment design epigenetic regulation epigenomics event cycle histone methylation improved in vivo malformation mortality neoplastic novel novel strategies pancreas development paralogous gene prevent programs promoter public health relevance repaired senescence transcriptome sequencing transmission process tumor

项目摘要

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长期以来研究转录的主要资金来源，

项目成果

期刊论文数量（123）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation.

DOI：
10.1002/mgg3.268
发表时间：
2017-03
期刊：
Molecular genetics & genomic medicine
影响因子：
2
作者：
Blackburn PR;Williams M;Cousin MA;Boczek NJ;Beek GJ;Lomberk GA;Urrutia RA;Babovic-Vuksanovic D;Klee EW
通讯作者：
Klee EW

Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts.

DOI：
10.1158/1078-0432.ccr-12-0560
发表时间：
2012-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Kitange GJ;Mladek AC;Carlson BL;Schroeder MA;Pokorny JL;Cen L;Decker PA;Wu W;Lomberk GA;Gupta SK;Urrutia RA;Sarkaria JN
通讯作者：
Sarkaria JN

Functional characterization of a GFAP variant of uncertain significance in an Alexander disease case within the setting of an individualized medicine clinic.

DOI：
10.1002/ccr3.655
发表时间：
2016-09
期刊：
CLINICAL CASE REPORTS
影响因子：
0.7
作者：
Boczek, Nicole J;Sigafoos, Ashley N;Zimmermann, Michael T;Maus, Rachel L;Cousin, Margot A;Blackburn, Patrick R;Urrutia, Raul;Clark, Karl J;Patterson, Marc C;Wick, Myra J;Klee, Eric W
通讯作者：
Klee, Eric W

The sunset of somatic genetics and the dawn of epigenetics: a new frontier in pancreatic cancer research.