Networks for functional regulation of pancreatic acinar-ductal metaplasia and epithelial plasticity

胰腺腺泡导管化生和上皮可塑性的功能调节网络

• 批准号: 9977159
• 负责人: Anil K Rustgi
• 金额: $ 36.45万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977159
• 关键词: 3-Dimensional; Acinar Cell; Acute; Cells; Chronic; Data; Development; Duct (organ) structure; Ductal Epithelial Cell; Epigenetic Process; Epithelial; Epithelium; Exocrine pancreas; Expression Profiling; Family; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Health; Homeobox; Hour; Human; Impairment; Inflammation; Injury; Knock-out; Knockout Mice; Lesion; Maintenance; Mediating; Metaplasia; Mus; Natural regeneration; Oncogenic; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Injury; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pancreatitis; Population; Preneoplastic Conditions; Process; Publishing; Recovery; Regenerative response; Regulation; Research; Risk Factors; Role; Testing; Therapeutic; Tissues; Transcriptional Regulation; United States; acute pancreatitis; base; carcinogenesis; chronic pancreatitis; design; in vivo; innovation; insight; interest; member; mouse model; mutant; novel; novel strategies; novel therapeutics; pancreatic cancer model; premalignant; promoter; repaired; tissue regeneration; tissue repair; transcription factor

PROJECT SUMMARY The exocrine pancreas has a remarkable ability to regenerate after injury, as illustrated in acute pancreatitis, and subsets of chronic pancreatitis. Acinar-ductal metaplasia (ADM) is critical in the ability of the exocrine pancreas to regenerate or permit progression to a preneoplastic state (pancreatic intraepithelial neoplasia or PanIN). Expression of oncogenic Kras* (=mutant Kras) in the mouse pancreas leads to formation of PanIN lesions with long latency, indicating the need for genetic and possibly epigenetic “second hits”. Chronic pancreatitis is recognized as a strong risk factor for pancreatic ductal adenocarcinoma (PDA) in humans. In mouse models of pancreatic cancer, induction of either acute or chronic pancreatitis results in tissue-wide ADM that is followed by rapid repair (we designate this as “Adaptive” ADM). However, in the presence of oncogenic Kras*, repair is impaired and ADM progresses to PanIN lesions (we designate this as “Oncogenic” ADM). Currently, the mechanisms underlying the formation of ADM and how ADM progresses to PanIN in the presence of mutant Kras* remain unknown. Recently, our group performed gene expression analysis of murine ductal cells isolated from the developing pancreas, acute pancreatitis (ADM), and PanIN expressing oncogenic KrasG12D, and compared the expression profiles to that of normal pancreatic ductal cells, resulting in nearly 80 potential genes of interest. Prrx1 (paired-related homeobox 1) was the most differentially regulated transcription factor in all three processes, followed by Etv5, a member of the Ets family of transcriptional factors. Based upon compelling published and preliminary data, we hypothesize that Etv5 and Prrx1 are involved in the initiation and maintenance of ADM, respectively, following pancreatitis. Furthermore, we hypothesize that this regulation allows for subsequent transformation by oncogenic Kras*, thereby promoting progression to PanIN. This hypothesis will be tested through the following interrelated Specific Aims: (1) To determine if Prrx1 is required for ADM and PanIN following pancreatic injury; (2) To elucidate the relationship between Etv5 and Sox9 in the functional regulation of ADM; and (3) To identify and evaluate gene targets of Prrx1 and iKras* (inducible mutant Kras) in the development of “Oncogenic” ADM (to PanIN). This aim will identify effectors of Prrx1 and iKras*. Our innovative and integrated research will define the transcriptional regulation of ADM and provide a basis for new perspectives in the therapy of pancreatitis and PanIN.

项目总结