TBEL Project 2

TBEL项目2

基本信息

批准号：
10708202
负责人：
ANIRBAN MAITRA
金额：
$ 33.2万
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/10708202
关键词：
3-Dimensional Abdomen Accounting Affect Alleles Biochemical Biogenesis Cell Line Cell Survival 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 Knockout Mice 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 Phase I Clinical Trials Phosphorylation Inhibition 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 cancer invasiveness clinic ready 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 pharmacologic proteostasis reconstruction response tool tumor tumor microenvironment tumor progression

3-Dimensional Abdomen Accounting Affect Alleles Biochemical Biogenesis Cell Line Cell Survival 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 Knockout Mice 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 Phase I Clinical Trials Phosphorylation Inhibition 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 cancer invasiveness clinic ready 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 pharmacologic proteostasis reconstruction response tool tumor tumor microenvironment tumor progression

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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 - 摘要胰腺肿瘤（PCNS）的估计患病率在20-30％之间，导管内乳头状含量在20-30％之间粘液性肿瘤（IPMN）占其中一半的一半。取决于形态，位置和遗传学 IPMN可以是高风险发展的胰腺导管腺癌（PDAC），因此减少患者的生存。虽然RNF43仅在一小部分PDAC中突变，但RNF43突变是尽管RNF43已被确定为Wnt的负调节剂结直肠癌和其他临床前模型的信号传导，包括PDAC，Wnt的1期临床试验 RNF43突变固体癌症（包括PDAC）的抑制剂已被证明令人失望。其他 RNF43的器官特定功能可能对IPMN进展可能是很大的优势。利用条件 RNF43的敲除小鼠模型在KRAS突变的上下文中，我们发现RNF43废除了线粒体 RNF43损失的属性和功能改善了线粒体质量控制，增强了展开的蛋白质反应（UPR）和ER应力。这些发现使我们假设RNF43的损失可能会放松管制这些细胞器的串扰，以维持蛋白质抑制，代谢控制和细胞存活。在KRAS的背景下，采用自我鼠标模型来实现RNF43的功能损失（在 Maitra Lab博士），主要基因工程细胞系（在Lyssiotis博士实验室生成）和人类IPMN 衍生的类器官（在伍德博士实验室中生成；请参阅项目3），我们建议追求以下目标：首先，我们将研究RNF43是否调节线粒体动力学，包括生物发生，裂变，融合线粒体抑制IPMN发病机理（AIM 1）。此外，我们将调查RNF43是否阻止IPMN 通过管理ER-线粒体动力学来限制ER应力，通过限制ER应力（AIM 2）。最后，我们会的确定RNF43的损失是否为持续的Oxphos创造了合成的本质（AIM 1）和 OXPHOS抑制是否/如何影响自我围绕KRC模型的多步骤进展胰腺肿瘤（AIM 3）。总体而言，这些研究将阐明RNF43在线粒体质量控制，ER线粒体动力学以及这如何影响IPMN发病机理和进展。