Differential Wnt Dependencies in Colon Epithelium.

结肠上皮细胞中不同的 Wnt 依赖性。

基本信息

批准号：
10739179
负责人：
GEORGE ENG
金额：
$ 19.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739179
关键词：
APC gene APC mutation Adenocarcinoma Advisory Committees Affect Agonist Award Biological Assay Biomedical Engineering CRISPR interference Caliber Cancer Biology Cancer Model Carcinoma Cell Nucleus Cell Proliferation Cell physiology Cells Clinical Colon Colon Adenocarcinoma Colon Carcinoma Colonic Adenoma Colonic Neoplasms Colorectal Cancer Complex Data Dependence Development Plans Diet Dose Elements Engineering Ensure Epithelium Essential Genes Exhibits Foundations Frequencies General Hospitals Genes Genetic Glycogen Synthase Kinase 3 Growth Human Institution Intestines KRAS2 gene Knock-out Lesion Location Loss of Heterozygosity Maintenance Malignant Neoplasms Massachusetts Medical Mentors Modeling Moderna COVID-19 vaccine Molecular Mus Mutate Mutation Normal Cell Normal tissue morphology Oncogenic Organoids Pathologist Pathway interactions Patients Physicians Polypectomy Pre-Clinical Model Protein Kinase Proteins Recording of previous events Research Resources Rho-associated kinase Scientist Signal Transduction Specimen Stereotyping TP53 gene Technology Therapeutic Time Toxic effect Training WNT Signaling Pathway Wnt proteins Work adenoma beta catenin clinical care colon cancer treatment human model improved in vivo inhibitor knock-down loss of function loss of function mutation mouse model mutant nanoparticle nanoparticle delivery neoplastic cell novel pharmacologic progenitor programs small molecule inhibitor stem cells success targeted treatment transcriptome sequencing transcriptomics tumor tumor growth

项目摘要

Project Summary/Abstract This proposal details a five-year training plan for the development of a research program focused on elucidating the therapeutic potential of superimposed additional Wnt signaling on colonic neoplasia. The molecular driver shared across the vast majority of colonic neoplasms is constitutive Wnt signaling, most commonly caused by loss of function mutations in the APC gene. The loss of function of APC permits beta catenin to constitutively translocate to the nucleus and induce the formation of colonic adenomas which can further mutate into colon cancer. To date, strategies to inhibit Wnt signaling for therapeutic purposes have failed. However, other elements of the beta catenin destruction complex that work with APC, such as GSK3 alpha and beta can be pharmacologically inhibited. Therefore, instead of inhibiting Wnt signaling, and informed by the concept that a “just right” amount of Wnt signaling may be selected for in tumor cells, we hypothesized additional Wnt signaling would be deleterious to tumor cells but would simultaneously enhance the function of normal cells. This project will elucidate fundamental dependencies of Wnt signaling in normal tissues as well as tumors. Ultimately, I believe this will engender a specific therapy for adenomas, to which there is no existing medical therapy other than polypectomy, and additionally provide a broadly applicable and potentially safe approach to treat colorectal cancer. I am clinically trained pathologist and physician scientist seeking K08 support for mentored research. This work will be mentored by Prof. Omer Yilmaz and Prof. Robert Langer. Prof. Yilmaz is a pathologist and physician-scientist, and studies the effects of diet on intestinal stem cells and state- of-the-art intestinal organoid models. Prof. Langer has fundamentally transformed and defined biomedical engineering, is the most cited engineer in history, and most recently his expertise in nanoparticle delivery provided the foundation for the Moderna COVID-19 vaccine. The work will be conducted at the Massachusetts Institute of Technology and Massachusetts General Hospital, both world class institutions of the highest caliber. I have assembled a scientific advisory committee consisting of world class cancer biologists to help guide my scientific progress, consisting of Prof. Tyler Jacks, Prof. Michael Yaffe, and Prof. William Kaelin. This K08 mentored research award will ensure I have the time and resources to develop expertise in cancer biology and explore this promising therapeutic and biologically intriguing concept of increased Wnt signaling to specifically treat colonic neoplasia. This topic will provide ample substrate for me to grow as an independent physician scientist.

项目概要/摘要该提案详细介绍了一项针对开发研究项目的五年培训计划，重点关注阐明叠加额外 Wnt 信号传导对结肠肿瘤的治疗潜力。绝大多数结肠肿瘤共有的分子驱动因素是组成型 Wnt 信号传导，最常见的是由 APC 基因功能缺失突变引起。 APC 允许 β 连环蛋白组成型易位至细胞核并诱导形成结肠腺瘤可进一步突变为结肠癌。迄今为止，抑制 Wnt 的策略已出现。然而，β连环蛋白的其他元件却失败了。与 APC 一起作用的破坏复合物，例如 GSK3 α 和 β，可以在药理上发挥作用因此，不是抑制Wnt信号传导，而是通过“恰到好处”的概念来告知。肿瘤细胞中可以选择 Wnt 信号传导的量，我们追求额外的 Wnt 信号传导对肿瘤细胞有害，但同时会增强正常细胞的功能。该项目将阐明正常组织以及 Wnt 信号传导的基本依赖性最终，我相信这将产生一种针对腺瘤的特殊疗法，而目前还没有这种疗法。除息肉切除术之外的现有医学疗法，并另外提供了广泛适用和一种治疗结直肠癌的潜在安全方法。我是一名接受过临床培训的病理学家和医师科学家，正在寻求 K08 支持以进行指导性研究。这项工作将由 Omer Yilmaz 教授和 Robert Langer 教授指导。病理学家和医师科学家，研究饮食对肠道干细胞和状态的影响兰格教授从根本上改变和定义了最先进的肠道类器官模型。生物医学工程，是历史上被引用次数最多的工程师，最近他的专业知识是纳米粒子递送为 Moderna COVID-19 疫苗奠定了基础。在麻省理工学院和麻省总医院进行我组建了一个最高水平的世界级机构的科学顾问委员会。由世界一流的癌症生物学家组成，帮助指导我的科学进步，包括教授。 Tyler Jacks、Michael Yaffe 教授和 William Kaelin 教授将获得该 K08 指导研究奖。确保我有时间和资源来发展癌症生物学方面的专业知识并探索这一点增加 Wnt 信号传导以特异性地治疗和生物学上有趣的概念治疗结肠肿瘤将为我作为一个独立的成长提供充足的基础。医师科学家。