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TBEL Project 2

TBEL项目2

基本信息

批准号：
10518938
负责人：
ANIRBAN MAITRA
金额：
$ 39.2万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518938
关键词：
3-Dimensional Abdomen Accounting Affect Alleles Biochemical Biogenesis Cell Line Cell Survival Clinic Collaborations Colorectal Cancer Cyst Cystic Lesion Data Dependence Diagnosis Drops Excision Exhibits Fibroblasts Frequencies Genetic Genetic Engineering Histopathology Human Image In Vitro Indolent Intervention KRAS2 gene Lesion Location Malignant Neoplasms Malignant neoplasm of pancreas Membrane Potentials Metabolic Control Metabolic Pathway Metabolism Mitochondria Modeling Molecular Molecular Biology Techniques Morphology Mucinous Neoplasm Mus Mutate Mutation Nature Operative Surgical Procedures Organ Organelles Organoids Oxidative Phosphorylation Pancreas Pancreatic Cyst Pancreatic Ductal Adenocarcinoma Pancreatic cystic neoplasia Papillary Pathogenesis Patients Pharmacology Phase I Clinical Trials Pre-Clinical Model Prevalence Probability Property Proteins Quality Control Recording of previous events Reporter Reporting Respiration Role Site Solid TP53 gene Testing Tissues WNT Signaling Pathway Wood material base cancer invasiveness clinical application conditional knockout endoplasmic reticulum stress functional loss genetic approach genetically modified cells high risk improved in vitro Model in vivo inhibitor insight mitochondrial metabolism mouse model mutant neoplastic novel pancreatic ductal adenocarcinoma model proteostasis reconstruction response tool tumor tumor microenvironment tumor progression

项目摘要

PROJECT 2 – ABSTRACT The estimated prevalence of pancreatic cystic neoplasms (PCNs) is between 20–30% with intraductal papillary mucinous neoplasm (IPMNs) accounting for half of them. Depending on the morphology, location, and genetics IPMNs can be of high-risk developing pancreatic ductal adenocarcinoma (PDAC) and as such significantly diminishing patient’s survival. While RNF43 is only mutated in a small fraction of PDAC, RNF43 mutations are prevalent in a high frequency in IPMNs. Although RNF43 has been identified as a negative regulator of Wnt signaling in colorectal cancers and other preclinical models including PDAC, a phase 1 clinical trial of a Wnt inhibitor in patients with RNF43 mutated solid cancers (including PDAC) has been proven disappointing. Other likely organ specific functions of RNF43 might be of great advantage for IPMN progression. Utilizing a conditional knockout mouse model of RNF43 in context of Kras mutation we found that RNF43 abrogates the mitochondrial properties and functions while loss of RNF43 improved mitochondrial quality control, increased unfolded protein response (UPR) and ER stress. These findings let us hypothesize that loss of RNF43 may deregulate the crosstalk of these organelles in order to maintain proteostasis, metabolic control, and cell survival. Employing an autochthonous mouse model for functional loss of RNF43 in the context of Kras (generated in the Dr. Maitra lab), primary genetically engineered cell lines (generated in the Dr. Lyssiotis lab) and human IPMN derived organoids (generated in the Dr. Wood lab; see Project 3) we propose to pursue the following aims: First we will investigate whether RNF43 regulates mitochondrial dynamics including biogenesis, fission, fusion and mitophagy to inhibit IPMN pathogenesis (Aim 1). Further, we will investigate whether RNF43 blocks IPMN pathogenesis by limiting ER stress through management of ER-mitochondrial dynamics (Aim 2). Lastly, we will determine whether loss of RNF43 creates a synthetic essentiality for sustained OXPHOS (Aim 1) and whether/how OXPHOS inhibition impacts the multistep progression in an autochthonous KRC model of pancreatic cystic neoplasia (Aim 3). Overall, these studies will elucidate the functional role of RNF43 in mitochondria quality control, ER-mitochondrial dynamics and how this impacts IPMN pathogenesis and progression.

项目2 -摘要