TBEL Project 2

TBEL项目2

基本信息

  • 批准号:
    10518938
  • 负责人:
  • 金额:
    $ 39.2万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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专利数量(0)

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ANIRBAN MAITRA其他文献

ANIRBAN MAITRA的其他文献

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{{ truncateString('ANIRBAN MAITRA', 18)}}的其他基金

TBEL Admin Core
TBEL 管理核心
  • 批准号:
    10518936
  • 财政年份:
    2022
  • 资助金额:
    $ 39.2万
  • 项目类别:
Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer
肿瘤微环境串扰导致胰腺癌早期病变
  • 批准号:
    10518935
  • 财政年份:
    2022
  • 资助金额:
    $ 39.2万
  • 项目类别:
TBEL Admin Core
TBEL 管理核心
  • 批准号:
    10708200
  • 财政年份:
    2022
  • 资助金额:
    $ 39.2万
  • 项目类别:
Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer
肿瘤微环境串扰导致胰腺癌早期病变
  • 批准号:
    10708199
  • 财政年份:
    2022
  • 资助金额:
    $ 39.2万
  • 项目类别:
TBEL Project 2
TBEL项目2
  • 批准号:
    10708202
  • 财政年份:
    2022
  • 资助金额:
    $ 39.2万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10226091
  • 财政年份:
    2019
  • 资助金额:
    $ 39.2万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10415971
  • 财政年份:
    2019
  • 资助金额:
    $ 39.2万
  • 项目类别:
Translational Applications in an Animal Model of Pancreatic Cystic Neoplasm and Cancer
胰腺囊性肿瘤和癌症动物模型中的转化应用
  • 批准号:
    9904574
  • 财政年份:
    2018
  • 资助金额:
    $ 39.2万
  • 项目类别:
Wnt/?-catenin Signaling in Pancreatic Oncogenesis
胰腺肿瘤发生中的 Wnt/β-catenin 信号转导
  • 批准号:
    9565530
  • 财政年份:
    2017
  • 资助金额:
    $ 39.2万
  • 项目类别:
Wnt/?-catenin Signaling in Pancreatic Oncogenesis
胰腺肿瘤发生中的 Wnt/β-catenin 信号转导
  • 批准号:
    10406280
  • 财政年份:
    2017
  • 资助金额:
    $ 39.2万
  • 项目类别:

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