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

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 – 摘要导管内乳头状胰腺囊性肿瘤 (PCN) 的估计患病率在 20-30% 之间粘液性肿瘤 (IPMN) 占其中的一半，具体取决于形态、位置和遗传学。 IPMN 可能是高风险的胰腺导管腺癌 (PDAC)，因此显着虽然 RNF43 仅在一小部分 PDAC 中发生突变，但 RNF43 突变却会降低患者的生存率。尽管 RNF43 已被确定为 Wnt 的负调节因子，但在 IPMN 中普遍存在。结直肠癌和其他临床前模型中的信号转导，包括 PDAC（Wnt 的 1 期临床试验） RNF43 突变实体癌（包括 PDAC）患者的抑制剂已被证明令人失望。 RNF43 可能的器官特异性功能可能对利用条件性进展有很大优势。在 Kras 突变背景下的 RNF43 敲除小鼠模型中，我们发现 RNF43 消除了线粒体特性和功能，同时 RNF43 的缺失改善了线粒体质量控制，增加了未折叠蛋白这些发现让我们推测 RNF43 的缺失可能会放松对内质网应激的调节。这些细胞器的串扰以维持蛋白质稳态、代谢控制和细胞存活。采用本地小鼠模型来研究 Kras 背景下 RNF43 功能丧失的情况（在 Maitra 博士实验室）、原代基因工程细胞系（在 Lyssiotis 博士实验室生成）和人类 IPMN 衍生类器官（在 Wood 博士实验室生成；参见项目 3），我们建议实现以下目标：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、融合和线粒体自噬抑制 IPMN 发病机制（目标 1）此外，我们将研究 RNF43 是否阻断 IPMN。通过管理 ER 线粒体动力学来限制 ER 应激（目标 2）。确定 RNF43 的缺失是否会产生持续 OXPHOS 的合成必要性（目标 1）以及 OXPHOS 抑制是否/如何影响本地 KRC 模型中的多步进展总体而言，这些研究将阐明 RNF43 在胰腺囊性肿瘤中的功能作用。线粒体质量控制、ER 线粒体动力学及其如何影响 IPMN 发病机制和进展。