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.

项目摘要/摘要该提案详细介绍了针对研究计划的五年培训计划，该计划的重点是阐明在结肠肿瘤上叠加额外的Wnt信号的治疗潜力。在绝大多数结肠肿瘤中共享的分子驱动器是构成的Wnt 信号传导，最常见的是APC基因中功能突变的丧失。功能丧失 APC的允许β链氨酸蛋白蛋白蛋白链蛋白构成转移到核并诱导形成可以进一步突变为结肠癌的结肠腺瘤。迄今为止，抑制Wnt的策略用于热目的的信号失败。但是，Beta catenin的其他元素与APC一起使用的破坏复合物，例如GSK3 alpha和beta可以是药物的抑制。因此，与其抑制Wnt信号传导，并以这样的概念告知“恰到好处” 可以在肿瘤细胞中选择WNT信号的量，我们假设其他Wnt信号传导会对肿瘤细胞有害，但只会增强正常细胞的功能。该项目将阐明正常组织中Wnt信号的基本依赖性以及最终，我相信这将为腺瘤提供特定的疗法，没有除息肉切除术以外的现有医疗疗法，并提供广泛适用的治疗大肠癌的潜在安全方法。我是经过临床训练的病理学家和身体科学家，寻求K08支持指导研究的支持。这项工作将由Omer Yilmaz教授和Robert Langer教授召集。 Yilmaz教授是病理学家和身体科学家，研究饮食对肠道干细胞和状态的影响艺术肠道器官模型。 Langer教授从根本上进行了改造和定义生物医学工程是历史上最引人入胜的工程师，最近他的专业知识纳米颗粒的递送为现代covid-19疫苗提供了基础。工作将是在马萨诸塞州技术与马萨诸塞州综合医院进行最高口径的世界一流机构。我已经组建了一个科学咨询委员会由世界一流的癌症生物学家组成，以帮助指导我的科学进步，包括教授泰勒·杰克斯（Tyler Jacks），迈克尔·雅菲（Michael Yaffe）教授和威廉·凯林（William Kaelin）教授。这个K08指导研究奖将确保我有时间和资源来发展癌症生物学专业知识并探讨这一点有希望的治疗和生物学上有趣的Wnt信号转导的概念治疗结肠肿瘤。这个话题将为我提供足够的基材，使我成为一个独立的基础医师科学家。