Elucidating the role of Fra1 in pancreatic Kras-driven acinar to ductal metaplasia

阐明 Fra1 在胰腺 Kras 驱动的腺泡到导管化生中的作用

• 批准号: 10537870
• 负责人: Alina Lin Li
• 金额: $ 4.73万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537870
• 关键词: 3-Dimensional; ATAC-seq; Academic Medical Centers; Acinar Cell; Acute; Advisory Committees; Affect; Agreement; Alleles; Amino Acid Motifs; Attenuated; Automobile Driving; Award; Back; Basic Science; Binding Sites; Biological Assay; CSF3 gene; Caerulein; Cell Culture Techniques; Cell Nucleus; Cells; Characteristics; Cholecystokinin; Chromatin; Colony-Stimulating Factor Receptors; Data Analyses; Development; Doctor of Philosophy; Dose; Doxycycline; Duct (organ) structure; Ductal Epithelial Cell; Epithelial; Epithelial Cells; FOSL1 gene; Fellowship; Fibroblasts; Fos-Related Antigens; Foundations; Functional disorder; Goals; Homeostasis; Individual; Inflammation; Injury; KRAS oncogenesis; KRAS2 gene; Knockout Mice; Knowledge; Lesion; Link; Maintenance; Mediator of activation protein; Medical center; Mentors; Metaplasia; Metaplastic Cell; Modeling; Molecular and Cellular Biology; Mutation; Oncogenic; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Injury; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Persons; Phenotype; Physicians; Population; Precipitation; Process; Public Health; Regulation; Research Personnel; Residencies; Resources; Role; Scientist; Signal Pathway; Signal Transduction; Techniques; Testing; Therapeutic Intervention; Tissues; Training; Translational Research; Universities; Up-Regulation; XCL1 gene; acute pancreatitis; analog; career; cell type; chromatin remodeling; chronic pancreatitis; combat; effective therapy; experience; innovation; insight; mouse model; mutant; new therapeutic target; novel; pancreatic metaplasia; pre-doctoral; progenitor; protein complex; response to injury; single cell sequencing; therapeutic target; three dimensional cell culture; tissue regeneration; transcription factor

PROJECT SUMMARY (ABSTRACT) Acute and chronic pancreatitis afflict millions of individuals in the US. Mouse models have revealed that acinar cells can de-differentiate after pancreatic injury to a progenitor-like cell type with ductal characteristics in a process termed acinar-to-ductal metaplasia (ADM). In the absence of oncogenic mutations, ADM lesions can resolve and reform the acinar compartment. However, in the presence of oncogenic Kras mutations, the ADM lesions can continue to de-differentiate to a pre-invasive pancreatic intraepithelial neoplasia (PanIN). The mechanisms that drive PanIN formation in the context of injury and oncogenic mutations are poorly understood, resulting in an absence of targets to combat the persistent ADM. We have identified previously through bulk ATAC-sequencing that the transcription factor Fra1 is differentially active only in the context of mutant Kras and acute inflammation. We have also generated a unique mouse model expressing inducible mutant KRAS (iKras) and Fra1 loxp alleles (Fra1 KO) in a pancreatic epithelial- specific manner. Our preliminary studies demonstrate that Fra1 loss attenuates ADM formation and stromagenesis compared to the FRA1 WT controls. The overarching goal of this proposal is to understand how FRA1 and its interacting partners, which constitute the AP-1 complex, govern ADM progression in the context of mutant Kras and inflammation. My hypothesis is that FRA1 is a central mediator of ADM. I will investigate the cell autonomous and non-cell autonomous effects driving FRA1 activation through the following interrelated Specific Aims: (1) Investigate how Fra1 remodels chromatin in ADM after induction of pancreatitis; (2) Elucidate the role of fibroblast-secreted G-CSF in Fra1 induction during pancreatitis. I will use novel mouse models, ex vivo 3D acinar and ADM cell cultures, and state-of-the-art single-cell sequencing and chromatin precipitation assays to conduct this study. This proposal also encompasses a translational aspect by proposing G-CSFR as a novel therapeutic target for the treatment of acute pancreatitis. Additionally, this project incorporates aspects of pathophysiology, molecular/cellular biology, and quantitative data analysis. This proposal provides me with a robust foundation in both experimental and quantitative analysis and broadens my fundamental knowledge of pancreatic epithelial cell homeostasis and plasticity. With the guidance from experienced mentors (Drs. Rustgi and Sims), my advisory committee and the rich array of resources at Columbia University Irving Medical Center, I will be able to complete my predoctoral PhD training. Completion of this critical milestone will set the stage for my long-term goal as a physician-scientist who conducts basic and translational research in an academic medical center with a focus on tissue inflammation, cellular identity and plasticity, and tissue regeneration.

项目总结（摘要）