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

人类结肠癌发生锯齿状途径机制阐明的计算方法

• 批准号: 10590985
• 负责人: Marmar Moussa
• 金额: $ 19.87万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590985
• 关键词: ATAC-seq; Anatomy; Appearance; Area; Atlases; Award; Biopsy; Cancer Biology; Cancerous; Carcinoma; Cause of Death; Cell Communication; Cells; Characteristics; Chromosomal Instability; Clinical; Clinical Markers; Collection; Colon; Colon Carcinoma; Colonic Polyps; Colorectal Cancer; Complement; Complex; Computers; Computing Methodologies; Connecticut; Data; Detection; Development Plans; Diagnosis; Dysplasia; Early Diagnosis; Epigenetic Process; Evolution; Excision; Formalin; Freezing; Gene Expression; Genes; Genomics; Goals; Heterogeneity; High grade dysplasia; Histologic; Histology; Histopathology; Human; Hyperplasia; Individual; Institution; Interdisciplinary Study; Lead; Lesion; Ligands; Link; MLH1 gene; Malignant - descriptor; Malignant Neoplasms; Maps; Measures; Mentors; Methylation; Microsatellite Instability; Modeling; Molecular; Molecular Profiling; Morphology; Mutation; Neighborhoods; Normal tissue morphology; Paraffin Embedding; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Physicians; Polypectomy; Polyps; Positioning Attribute; Precancerous Conditions; Prevention; Prevention program; Public Health; Publishing; Registries; Research; Research Personnel; Resolution; Risk; Sampling; Scientist; Series; Specimen; System; Testing; Tissue Sample; Training; United States; Universities; Work; adenoma; cancer genomics; cancer invasiveness; carcinogenesis; career; career development; cell community; cohort; colon cancer prevention; colon carcinogenesis; colorectal cancer prevention; exome; experience; human data; immune activation; immune cell infiltrate; improved; machine learning model; multiple omics; novel; premalignant; receptor; research and development; single cell analysis; single cell sequencing; tool; transcriptomic profiling; transcriptomics; tumor; tumor microenvironment; tumor-immune system interactions; tumorigenesis

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.

项目摘要 这个K25指导定量研究开发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-获得癌症方面的额外培训 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， 使PI成为完全独立的研究者。为此，穆萨博士召集了一个杰出的 由康涅狄格大学和哈佛大学的世界级科学家和医生组成的指导委员会 大学，并提供了一个全面的培训计划，以满足她的职业目标。此外，穆萨博士 研究目标是开发先进的计算方法来调查和模拟的机制， 人类结肠癌发生的锯齿状替代途径。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。 尽管近年来增加了结肠直肠癌（CRC）预防工作，但CRC仍然是第二大癌症。 是美国癌症死亡的主要原因CRC是由一系列遗传和表观遗传 两种途径描述的变化;研究充分的“常规腺瘤-癌序列”和 不太了解的“锯齿状路径”。锯齿状路径，其特征在于前体锯齿状 在过去的十年中，越来越多的研究表明，15 - 35%的CRC肿瘤发生是由这些病变引起的 并且甚至更多地在“间隔”CRC（I-CRC）中。因此，对监测和早期发现， 哪些高危病变沿着这条途径进展，以及如何进展。这是本提案的重点。 结肠癌发生的锯齿状病变途径的表征一直很困难，因为het- 在人类中缺乏全面的纵向数据。单细胞测序是最好的 这是研究异质性的工具，在这方面远远超过了组织学的力量。此外，丰富的 本研究可从PI机构获得数千份癌前和CRC样本。穆萨博士 将开发基因组和最先进的单细胞表观遗传（ATAC-Seq）的计算方法 和人类样本的转录组学分析，以准确表征不同的和亚型特异性的phe- notypes和阐明的机制，致癌发生在人类结肠通过锯齿状 途径（Aim 1）。此外，PI建议询问新的和突破性的空间分辨率 使用新的计算方法对存档福尔马林固定石蜡包埋（FFPE）样品进行转录组学研究， 在组织学相似的锯齿状病变/息肉中识别不同分子模式的方法 （目标2）。阐明前病变沿锯齿状通路沿着进展的机制将有助于了解 证明临床可预测性，并确定将预防扩展到息肉检测和切除之外的因素。