Computational approaches to the mechanistic elucidation of the serrated pathway of human colon carcinogenesis

项目总结 这份K25导师量化研究发展奖项目提案是为了让PI、Marmar博士 Moussa-一位经验丰富的计算机科学家和生物信息学家-获得额外的癌症培训 基因组学和细胞和分子癌症生物学需要领导一个跨学科的研究实验室和 让私家侦探做好准备，成为一名完全独立的调查员。为此，穆萨博士组装了一个杰出的 康涅狄格大学和哈佛大学世界级科学家和医生指导委员会 并提供了全面的培训计划，以满足她的职业目标。此外，穆萨博士的 研究目标是开发先进的计算方法来研究和模拟 人类结肠癌发生的另一种锯齿状途径。这项研究补充了穆萨博士的 职业发展计划，并促进她实现独立的道路。 尽管近年来结直肠癌(CRC)的预防努力有所增加，但CRC仍位居第二 在美国，癌症是主要的死亡原因。结直肠癌是从一系列遗传和表观遗传学发展而来的 由两条途径描述的变化；研究得很好的‘传统腺瘤-癌序列’和 鲜为人知的是“另类锯齿状通道”。锯齿状路径，以前驱体锯齿状为特征 在过去的十年里，越来越多的人被描述为导致15%-35%的结直肠癌发生 更多的是在“间隔”CRC(I-CRC)。因此，对监测和早期发现具有重要意义的是 哪些高危病变沿着这一途径进展，以及如何进展。这是这项提案的重点。 结肠癌发生的锯齿状病变途径的表征一直是困难的，因为het-2。 人类的异质性和缺乏全面的纵向数据。单细胞测序是最好的 研究异质性的工具，在这方面远远超过组织学的力量。此外，还有大量的 这项研究从国际癌症研究所获得了数千份癌前病变和结直肠癌样本。穆萨博士 将开发基因组和最先进的单细胞表观遗传学(ATAC-SEQ)的计算方法 并对人类样本进行转录分析，以准确地表征不同的和亚型特异性的Phe- 人类结肠通过锯齿状细胞发生癌变的机制 途径(Aim1)。此外，PI建议审问新的和开创性的空间分辨率 利用新型计算程序对档案福尔马林固定石蜡包埋(FFPE)样本的转录进行研究 在组织学上相似的锯齿状病变/息肉中识别不同分子模式的方法 (AIM2)。阐明锯齿状通路前驱病变进展的机制将有助于提高临床疗效。 证明临床可预测性，并确定远远超出息肉检测和切除的预防因素。

PROJECT SUMMARY This K25 Mentored Quantitative Research Development Award project proposal is to allow the PI, Dr. Marmar Moussa - an experienced Computer Scientist and Bioinformatician - to obtain additional training in cancer genomics and cellular and molecular cancer biology needed to lead an interdisciplinary research lab and prepare the PI to become a fully independent investigator. To that end, Dr. Moussa assembled an outstanding mentoring committee of world-class scientists and physicians from University of Connecticut and Harvard University and provided a comprehensive training plan to meet her career goals. Additionally, Dr. Moussa’s research goal is to develop advanced computational approaches to investigate and model the mechanisms of the alternative serrated pathway of human colon carcinogenesis. This research complements Dr. Moussa’s career development plan and promotes her path to achieve independence. Despite increased colorectal cancer (CRC) prevention efforts in recent years, CRC remains the second leading cause of death from cancer in the United States. CRC develops from a series of genetic and epigenetic changes described by two pathways; the well-studied ’conventional adenoma-carcinoma sequence’ and the less understood ’alternative serrated pathway’. The serrated pathway, characterized by the precursor Serrated Lesions, is increasingly described over the past decade to be contributing to 15 - 35% of CRC tumorigenesis and even more in ’interval’ CRC (I-CRC). It is therefore significant for surveillance and early detection to identify which at-risk lesions progress along this pathway, and how. This is the focus of this proposal. Characterization of the serrated lesion pathway of colon carcinogenesis has been difficult due to the het- erogeneity and the absence of comprehensive longitudinal data in humans. Single cell sequencing is the best tool for studying heterogeneity, and far exceeds the power of histology in this regard. In addition, a wealth of thousands of pre-cancerous and CRC samples is available to this study from the PI’s institution. Dr. Moussa will develop computational approaches to the genomic, and state-of-the-art single cell epigenetic (ATAC-Seq) and transcriptomic analyses of human samples to accurately characterize distinct and subtype-specific phe- notypes and elucidate the mechanisms by which carcinogenesis occurs in the human colon via the serrated pathway (Aim1). Additionally, the PI proposes interrogating the new and groundbreaking spatially-resolved transcriptomics of archival Formalin Fixed Paraffin Embedded (FFPE) samples using novel computational ap- proaches to identify distinct molecular patterns within otherwise histologically similar serrated lesions/polyps (Aim2). Elucidating the mechanisms of precursor lesion progression along the serrated pathway will help im- prove clinical predictability and identify factors that extend prevention well beyond polyp detection and removal.