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; 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指导的定量研究开发奖项目建议是允许PI，Marmar博士 穆萨（Moussa） - 经验丰富的计算机科学家和生物信息学家 - 获得癌症的额外培训 基因组学，细胞和分子癌生物学需要领导跨学科研究实验室和 准备PI成为完全独立的研究者。为此，Moussa博士组建了一个杰出的 康涅狄格大学和哈佛大学的世界一流科学家和医师的指导委员会 大学并提供了一项全面的培训计划，以实现她的职业目标。此外，穆萨博士 研究目标是开发先进的计算方法，以调查和建模 人类结肠癌发生的替代性锯齿途径。这项研究完成了Moussa博士的 职业发展计划并促进了她实现独立的道路。 尽管近年来结直肠癌（CRC）预防工作增加，但CRC仍然是第二个 美国癌症死亡的主要原因。 CRC从一系列遗传和表观遗传学发展 通过两个途径描述的变化；经过充分研究的“常规腺瘤 - 癌序列”和 少了解“替代锯齿状途径”。锯齿状的途径，其特征是前体锯齿 在过去的十年中，病变越来越多地描述为CRC肿瘤发生的15-35％ 甚至更多的“间隔” CRC（I-CRC）。因此，对于监视和早期检测是重要的 哪些高危病变沿着这条途径进行，以及如何进行。这是该提议的重点。 由于HET- 人类中没有全面的纵向数据。单细胞测序是最好的 研究异质性的工具，在这方面远远超过了组织学的力量。此外，很多 PI机构可以为这项研究提供数千种癌前和CRC样本。穆萨博士 将开发用于基因组和最先进的单细胞表观遗传学（ATAC-SEQ）的计算方法 和人类样品的转录组分析，以准确表征不同的和亚型特异性的PHE- Notypes并阐明了通过锯齿状在人类结肠中发生癌变的机制 途径（AIM1）。此外，PI提案询问了新的和开创性的空间分辨 福音福尔马林固定石蜡嵌入（FFPE）样品的转录组学使用新颖的计算AP- 在本质上相似的锯齿状病变/息肉中识别不同分子模式的方法 （AIM2）。阐明前体病变沿锯齿状途径的机制将有助于 证明临床可预测性并确定将预防范围扩展到息肉检测和去除之外的因素。