Differential Wnt Dependencies in Colon Epithelium.

项目总结/摘要 该提案详细介绍了一项五年培训计划，旨在制定一项研究计划，重点是 阐明叠加的额外Wnt信号传导对结肠瘤形成的治疗潜力。 绝大多数结肠肿瘤共有的分子驱动因子是组成性Wnt 信号传导，最常见的是由APC基因中的功能缺失突变引起的。功能丧失 APC的表达允许β连环蛋白组成性地易位到细胞核并诱导细胞核的形成。 结肠腺瘤会进一步突变成结肠癌。迄今为止，抑制Wnt的策略 用于治疗目的的信号传导已经失败。然而，β连环蛋白的其他成分 与APC一起工作的破坏复合物，如GSK 3 α和β，可以被破坏。 压抑因此，与其抑制Wnt信号传导，并告知的概念，一个“刚刚好” 在肿瘤细胞中可以选择Wnt信号的量，我们假设额外的Wnt信号 对肿瘤细胞有害，但同时增强正常细胞的功能。 该项目将阐明Wnt信号在正常组织中的基本依赖性，以及 肿瘤的最终，我相信这将产生一种针对腺瘤的特定疗法， 除了息肉切除术之外的现有医学疗法，并且另外提供了广泛适用的和 潜在的安全方法来治疗结直肠癌。 我是临床训练有素的病理学家和医生科学家寻求K 08支持辅导研究。 这项工作将由奥默耶尔马兹教授和罗伯特兰格教授指导。Yilmaz教授是一位 病理学家和物理学家，科学家，研究饮食对肠道干细胞和状态的影响， 最先进的肠道类器官模型兰格教授从根本上改变并定义了 生物医学工程，是历史上被引用次数最多的工程师，最近他的专长是 纳米颗粒递送为Moderna COVID-19疫苗提供了基础。这项工作将 在马萨诸塞州理工学院和马萨诸塞州总医院进行， 世界一流的机构的最高水平。我召集了一个科学顾问委员会 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，由教授。 泰勒杰克，教授迈克尔亚菲，和教授威廉凯林。K 08指导研究奖将 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。 有前途的治疗和生物学上有趣的概念，增加Wnt信号传导， 治疗结肠肿瘤。这个主题将提供充足的基板，我成长为一个独立的 医学科学家

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.