Targeting plasma membrane spatial dynamics to suppress aberrant Wnt signaling

靶向质膜空间动力学抑制异常的 Wnt 信号传导

基本信息

  • 批准号:
    10630909
  • 负责人:
  • 金额:
    $ 53.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-03 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

SUMMARY Dysregulation of the Wnt signaling pathway has been linked to cancer in multiple tissues. For example, most colorectal cancer (CRC) cases (~90%) are associated with aberrant Wnt signaling, due in part to mutations (>80%) associated with Adenomatous polyposis coli (APC), a multi-functional tumor suppressor gene. Unfortunately, attempts to target aberrant Wnt signaling using drugs still face multiple hurdles due to poor tumor cell targeting, negative side effects associated with required long-term treatments and a poor understanding of the mechanisms of action. Consequently, there is an urgent need to further assess non-toxic Wnt targeted therapeutic approaches. Therefore, this proposal seeks to develop novel membrane targeted therapeutic approaches to abate abnormal Wnt signaling in the colon. The scientific premise that supports the proposed research on Wnt receptor plasma membrane spatial dynamics is based on the fact that Wnt receptors and their signaling are required for CRC development within the context of a mutant APC background. This goal is supported by our novel discovery indicating that APC mutations causing abnormal Wnt signaling are associated with biophysical distortions in the cell plasma membrane, thereby promoting Wnt receptor nanoclustering and downstream signaling. We have also demonstrated that select membrane targeted dietary bioactives (MTDBs) can restore normal plasma membrane signaling by correcting cancer- causing biophysical distortions in the cell surface. In order to unravel the intricacies of membrane-based cancer prevention strategies, we propose to use novel mouse, Drosophila (fruit fly) and human colon organoid model systems to elucidate the underlying mechanisms by which MTDBs reshape the cell plasma membrane to suppress aberrant Wnt signaling. In Aim 1, we will further probe how mutated (oncogenic) APC perturbs cholesterol homeostasis in the colonic crypt, thereby increasing plasma membrane order and lipid raft-dependent spatiotemporal dynamics. In Aim 2, we will test our hypothesis that oncogenic APC-induced changes in cholesterol homeostasis alters the spatiotemporal organization (nanoclustering) of Wnt signaling-associated receptors, thereby promoting aberrant signaling. Aim 3 will examine the ability of MTDBs to attenuate aberrant Wnt signaling and colonic neoplasia phenotypes associated with oncogenic APC in part by “normalizing” plasma membrane biophysical properties. Upon completion of our proposed work, we expect to elucidate precisely how MTDBs therapeutically modify the cell membrane to suppress aberrant Wnt signaling and tumor formation in the colon. We propose that our novel approach to reshape plasma membrane Wnt receptor nanoclusters is a feasible CRC prevention or therapeutic strategy.
总结 Wnt信号通路的失调与多种组织中的癌症有关。例如,在一个示例中, 大多数结直肠癌(CRC)病例(约90%)与异常Wnt信号相关,部分原因是 突变(>80%)与结肠腺瘤性息肉病(APC)相关,APC是一种多功能肿瘤抑制因子 基因不幸的是,使用药物靶向异常Wnt信号传导的尝试仍然面临多重障碍, 肿瘤细胞靶向性差,与所需长期治疗相关的负面副作用, 了解作用机制。因此,迫切需要进一步评估无毒 Wnt靶向治疗方法。因此,该提议寻求开发新型膜靶向 减少结肠中异常Wnt信号传导的治疗方法。科学前提支持 对Wnt受体质膜空间动力学的拟议研究是基于Wnt 受体及其信号传导是突变APC背景下CRC发展所必需的 背景这一目标得到了我们新发现的支持,表明APC突变引起的异常 Wnt信号传导与细胞质膜中的生物物理扭曲相关,从而促进Wnt信号传导。 受体纳米簇和下游信号传导。我们还证明了选择膜 有针对性的膳食生物活性物质(MTDB)可以通过纠正癌症来恢复正常的质膜信号传导, 导致细胞表面的生物物理扭曲。为了解开复杂的膜基 癌症预防策略,我们建议使用新的小鼠,果蝇(果蝇)和人类结肠类器官 模型系统,以阐明MTDBs重塑细胞质膜的潜在机制 抑制异常的Wnt信号 在目标1中,我们将进一步探讨突变的(致癌的)APC如何扰乱胆固醇稳态, 结肠隐窝,从而增加质膜秩序和脂筏依赖性时空动力学。 在目标2中,我们将检验我们的假设,即致癌APC诱导的胆固醇稳态改变, Wnt信号相关受体的时空组织(纳米簇),从而促进 异常信号目的3将检查MTDB减弱异常Wnt信号传导和结肠炎的能力。 与致癌APC相关的肿瘤形成表型部分通过“正常化”质膜生物物理 特性. 在完成我们提出的工作后,我们希望精确地阐明MTDBs治疗 修饰细胞膜以抑制异常Wnt信号传导和结肠中的肿瘤形成。我们提出 我们重塑质膜Wnt受体纳米簇的新方法是一种可行的CRC预防方法, 或治疗策略。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
scTenifoldKnk: An efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation.
  • DOI:
    10.1016/j.patter.2022.100434
  • 发表时间:
    2022-03-11
  • 期刊:
  • 影响因子:
    6.5
  • 作者:
    Osorio, Daniel;Zhong, Yan;Li, Guanxun;Xu, Qian;Yang, Yongjian;Tian, Yanan;Chapkin, Robert S.;Huang, Jianhua Z.;Cai, James J.
  • 通讯作者:
    Cai, James J.
Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.
  • DOI:
    10.1038/s41467-023-39640-w
  • 发表时间:
    2023-07-19
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Erazo-Oliveras, Alfredo;Munoz-Vega, Monica;Mlih, Mohamed;Thiriveedi, Venkataramana;Salinas, Michael L.;Rivera-Rodriguez, Jaileen M.;Kim, Eunjoo;Wright, Rachel C.;Wang, Xiaoli;Landrock, Kerstin K.;Goldsby, Jennifer S.;Mullens, Destiny A.;Roper, Jatin;Karpac, Jason;Chapkin, Robert S.
  • 通讯作者:
    Chapkin, Robert S.
Membrane therapy using DHA suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation.
  • DOI:
    10.1016/j.jlr.2021.100026
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    6.5
  • 作者:
    Fuentes NR;Mlih M;Wang X;Webster G;Cortes-Acosta S;Salinas ML;Corbin IR;Karpac J;Chapkin RS
  • 通讯作者:
    Chapkin RS
Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer.
  • DOI:
    10.1038/s43856-023-00336-3
  • 发表时间:
    2023-08-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Schmidt, Daniel R;Gramatikov, Iva Monique T;Sheen, Allison;Williams, Christopher L;Hurwitz, Martina;Dodge, Laura E;Holupka, Edward;Kiger, W S 3rd;Cornwall-Brady, Milton R;Huang, Wei;Mak, Howard H;Cormier, Kathleen S;Condon, Charlene;Dane Wittrup, K;Yilmaz, Omer H;Stevenson, Mary Ann;Down, Julian D;Floyd, Scott R;Roper, Jatin;Vander Heiden, Matthew G
  • 通讯作者:
    Vander Heiden, Matthew G
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Robert Stephen Chapkin其他文献

Robert Stephen Chapkin的其他文献

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{{ truncateString('Robert Stephen Chapkin', 18)}}的其他基金

Nutritional and clinical predictors of intestinal maturation and feeding tolerance in the preterm infant
早产儿肠道成熟和喂养耐受性的营养和临床预测因素
  • 批准号:
    10717469
  • 财政年份:
    2023
  • 资助金额:
    $ 53.69万
  • 项目类别:
Targeting plasma membrane spatial dynamics to suppress aberrant Wnt signaling
靶向质膜空间动力学抑制异常的 Wnt 信号传导
  • 批准号:
    10047029
  • 财政年份:
    2020
  • 资助金额:
    $ 53.69万
  • 项目类别:
Targeting plasma membrane spatial dynamics to suppress aberrant Wnt signaling
靶向质膜空间动力学抑制异常的 Wnt 信号传导
  • 批准号:
    10401939
  • 财政年份:
    2020
  • 资助金额:
    $ 53.69万
  • 项目类别:
Diet and the colonic exfoliome: a novel, non-invasive approach to testing interventions in humans
饮食和结肠脱落组:一种测试人类干预措施的新型非侵入性方法
  • 批准号:
    10603601
  • 财政年份:
    2020
  • 资助金额:
    $ 53.69万
  • 项目类别:
Targeting plasma membrane spatial dynamics to suppress aberrant Wnt signaling
靶向质膜空间动力学抑制异常的 Wnt 信号传导
  • 批准号:
    10252842
  • 财政年份:
    2020
  • 资助金额:
    $ 53.69万
  • 项目类别:
Dietary Flavonoids-Microbiota-Ah Receptor Interactions in the Gut
肠道中膳食黄酮类化合物-微生物群-Ah 受体的相互作用
  • 批准号:
    9791345
  • 财政年份:
    2018
  • 资助金额:
    $ 53.69万
  • 项目类别:
Dietary Flavonoids-Microbiota-Ah Receptor Interactions in the Gut
肠道中膳食黄酮类化合物-微生物群-Ah 受体的相互作用
  • 批准号:
    10247052
  • 财政年份:
    2018
  • 资助金额:
    $ 53.69万
  • 项目类别:
Dietary and microbial predictors of childhood obesity risk
儿童肥胖风险的饮食和微生物预测因素
  • 批准号:
    9892995
  • 财政年份:
    2017
  • 资助金额:
    $ 53.69万
  • 项目类别:
Role of Aryl Hydrocarbon Receptor in Microbiota-Colon Stem Cell Interactions
芳基烃受体在微生物群-结肠干细胞相互作用中的作用
  • 批准号:
    9102325
  • 财政年份:
    2016
  • 资助金额:
    $ 53.69万
  • 项目类别:
Molecular basis for dietary chemoprevention
饮食化学预防的分子基础
  • 批准号:
    10348744
  • 财政年份:
    2016
  • 资助金额:
    $ 53.69万
  • 项目类别:

相似海外基金

APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    7425971
  • 财政年份:
    2006
  • 资助金额:
    $ 53.69万
  • 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    7620114
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    2006
  • 资助金额:
    $ 53.69万
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APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    8260721
  • 财政年份:
    2006
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    $ 53.69万
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APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    7247167
  • 财政年份:
    2006
  • 资助金额:
    $ 53.69万
  • 项目类别:
APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    7132974
  • 财政年份:
    2006
  • 资助金额:
    $ 53.69万
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APC mutation and breast cancer: Prevention by curcumin
APC 突变与乳腺癌:姜黄素预防
  • 批准号:
    7813928
  • 财政年份:
    2006
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    $ 53.69万
  • 项目类别:
APC mutation and the initiation of colorectal cancer
APC突变与结直肠癌的发生
  • 批准号:
    nhmrc : 400251
  • 财政年份:
    2006
  • 资助金额:
    $ 53.69万
  • 项目类别:
    NHMRC Project Grants
Development of novel screening method by detection of APC mutation from colorectal cancer cells in stool
开发粪便中结直肠癌细胞APC突变检测新筛查方法
  • 批准号:
    17591404
  • 财政年份:
    2005
  • 资助金额:
    $ 53.69万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
饮食与结肠癌 APC 突变的相互作用
  • 批准号:
    2748805
  • 财政年份:
    1995
  • 资助金额:
    $ 53.69万
  • 项目类别:
DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
饮食与结肠癌 APC 突变的相互作用
  • 批准号:
    2111759
  • 财政年份:
    1995
  • 资助金额:
    $ 53.69万
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