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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：
10252842
负责人：
Robert Stephen Chapkin
金额：
$ 55.28万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
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

来源：
https://reporter.nih.gov/project-details/10252842
关键词：
APC gene APC mutation Abate Address Attenuated Automobile Driving Biochemical Biological Models Biophysics Cell Line Cell membrane Cell surface Cells Cholesterol Cholesterol Homeostasis Clustered Regularly Interspaced Short Palindromic Repeats Colon Colon Carcinoma Colorectal Cancer Data Development Drosophila genus Drug usage Engineering Face Goals Homeostasis Human Implant Intestines Lead Link Malignant Neoplasms Membrane Membrane Lipids Membrane Microdomains Midgut Modeling Mus Mutate Mutation Neoplasms Oncogenes Oncogenic Organoids Phenotype Plasma Cells Prevention strategy Proteolipids Receptor Activation Research Risk Role Signal Pathway Signal Transduction Testing Therapeutic Tissues Toxicology Transgenic Organisms Tumor Suppressor Genes Tumor Suppressor Proteins WNT Signaling Pathway Work base beta catenin biophysical properties cancer prevention colonic crypt colorectal cancer prevention colorectal cancer risk dietary driving force in vivo mouse model mutant nano nanocluster neoplastic cell novel novel strategies overexpression receptor self-renewal side effect spatiotemporal stem cells targeted treatment tumor tumorigenesis

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