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.

项目概要 这个 K25 指导定量研究发展奖项目提案是为了让 PI Marmar 博士 穆萨 - 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 需要领导跨学科研究实验室和基因组学以及细胞和分子癌症生物学 为此，穆萨博士组建了一支出色的团队，帮助 PI 成为一名完全独立的调查员。 康涅狄格大学和哈佛大学世界级科学家和医生组成的指导委员会 穆萨博士还为她提供了大学和全面的培训计划来实现她的职业目标。 研究目标是开发先进的计算方法来研究和建模机制 这项研究补充了穆萨博士的人类结肠癌发生的替代锯齿状途径。 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) 的预防工作有所增加，但结直肠癌仍然是第二大癌症 结直肠癌是美国癌症死亡的主要原因。 两种途径描述的变化；经过充分研究的“传统腺瘤-癌序列”和 较少被理解的“替代锯齿状路径”。锯齿状路径，其特征是前体锯齿状路径。 在过去十年中，越来越多的人认为病变导致了 CRC 肿瘤发生的 15 - 35% 因此，监测和早期检测识别具有重要意义。 哪些有风险的病变沿着这条途径进展，以及如何进展，这是本提案的重点。 由于异质性，结肠癌发生的锯齿状病变途径的表征一直很困难。 异质性和缺乏人类的全面纵向数据是最好的。 研究异质性的工具，并且在这方面远远超过组织学的力量。 PI 博士的机构为这项研究提供了数千份癌前病变和结直肠癌样本。 将开发基因组计算方法和最先进的单细胞表观遗传学（ATAC-Seq） 对人类样本进行转录组分析，以准确表征不同的和亚型特异性的苯丙胺 notypes 并通过锯齿状结构阐明人类结肠癌发生的机制 此外，PI 建议探究新的、突破性的空间分辨率。 使用新型计算应用程序对档案福尔马林固定石蜡包埋 (FFPE) 样本进行转录组学 在其他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）阐明前体病变沿着锯齿状通路进展的机制将有助于im- 证明临床可预测性并确定将预防范围远远超出息肉检测和切除范围的因素。