SEMIColon: Somatic Exploration of Mosaicism in Colon

SEMIColon：结肠镶嵌现象的体细胞探索

• 批准号: 10751575
• 负责人: Laurel Hiatt
• 金额: $ 4.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751575
• 关键词: Adenocarcinoma; Affect; Aging; Anatomy; Architecture; Benign; Biological; Biopsy; Cadaver; Cancer Etiology; Cell Proliferation; Cells; Cessation of life; Clinical; Colon; Colonic Diseases; Colonoscopy; Colorectal; Colorectal Cancer; Consensus; Detection; Development; Disease; Disease Management; Disease Progression; Dissection; European ancestry; Event; Frequencies; Genetic Predisposition to Disease; Hindgut; Incidence; Individual; Inflammatory Bowel Diseases; Institutional Review Boards; Investigation; Lasers; Left; Length; Link; Location; Malignant Neoplasms; Maps; Metadata; Methodology; Midgut; Monitor; Morbidity - disease rate; Mosaicism; Mutagenesis; Mutation; Mutation Analysis; Normal tissue morphology; Organ; Organism; Outcome; Pathogenesis; Pathologic Mutagenesis; Pathology; Patients; Pattern; Play; Polyps; Precision therapeutics; Predisposition; Reporting; Research; Resolution; Risk; Role; Sampling; Somatic Mutation; Space Perception; Standardization; Structure; Syndrome; Testing; Tissues; Universities; Utah; Variant; adenoma; biobank; body system; causal variant; cohort; colonic crypt; disorder risk; early onset colorectal cancer; fitness; gastrointestinal; genome sequencing; human disease; human tissue; improved; innovation; insight; microbiome; mortality; mosaic; screening; spatiotemporal; whole genome

Project Summary/Abstract If we understand the somatic mosaicism of healthy tissues and how this changes through pathogenesis, we will be better equipped to screen for, monitor, and treat disease. Somatic mutations play a central role in disease pathogenesis, from developmental syndromes to cancer, and there is growing consensus that somatic mosaicism in healthy tissue influences fitness and disease predisposition. New methodological breakthroughs enable the accurate detection of somatic mutations, mutation rates, and mutational signatures. Establishing a biological baseline of mosaic profiles in healthy and diseased tissue can facilitate the prediction of genetically-driven disease states and the optimization of disease management. By studying somatic mosaicism in healthy and diseased colon, I will gain insight into colorectal pathogenesis and establish a research framework to apply to other tissues. The colon is ideal for mosaic research, given its monoclonal crypts, elevated mutation rate, and well-studied architecture. There are also significant associations between somatic mosaicism and colorectal disease: somatic mutations are causative in colorectal cancer (CRC) and are proposed to contribute to inflammatory bowel disease (IBD). These diseases have well-established regional presentations, with distinct pathologies along the length of the colon, such as “right” and “left” CRC and differently-clustered subtypes of IBD. However, the genetic etiologies underlying these pathologies are unknown, given previous limitations in mosaic research. This proposal will examine the spatiotemporal dynamics of colonic mosaicism in the context of healthy tissue and pathogenesis. Evaluating mosaicism across the length of the colon will provide insight into whether region-specific mutagenesis, either endogenous or exogenous, explains variation in regional pathogenesis. A preliminary study by Lee-Six et al. reported variation in mutational signature proportions across the colon. However, this analysis was limited by its low sequencing coverage (~15x) and examination of a small number of colonic subregions in a small cohort. By leveraging access to cadaver tissue and colonoscopy samples in tandem with biological and computational advances, I will quantify mosaicism with greater resolution and capacity for hypothesis testing. This proposal will determine individual and cohort-based mutational rates by anatomic subsite of the colon and extract mutational signatures that indicate mutagenic processes, such as cellular proliferation or microbiome variation. I hypothesize that midgut- and hindgut-derived colonic structures will harbor distinct mutational signatures from unique mutagenesis and regionally distinct mutation rates. These mutational landscapes will likely overlap regionally with the spatially-linked findings of CRC and IBD, suggesting a role in pathogenesis. Completion of this proposal will then serve as an ideal framework to examine regional variation and pathogenesis in other tissues.

项目总结/摘要 如果我们了解健康组织的体细胞嵌合现象以及这种变化是如何通过 发病机制，我们将更好地筛选，监测和治疗疾病。体细胞突变 在从发育综合征到癌症的疾病发病机制中起着核心作用， 健康组织中的体细胞嵌合体影响健康和疾病易感性。新 方法学上的突破使得能够准确检测体细胞突变、突变率和 变异特征在健康和患病组织中建立镶嵌分布的生物基线可以 有助于预测遗传驱动的疾病状态和优化疾病管理。 通过研究健康和患病结肠的体细胞嵌合现象，我将深入了解结直肠癌的发病机制， 发病机制，并建立适用于其他组织的研究框架。结肠是镶嵌的理想部位 研究，鉴于其单克隆隐窝，突变率升高，以及良好的研究架构。也有 体细胞嵌合现象与结直肠疾病之间的显著关联：体细胞突变是病因 在结直肠癌（CRC）中，并且被认为是导致炎症性肠病（IBD）的原因。这些 疾病具有明确的区域表现，沿着结肠长度具有不同的病理学， 例如“右”和“左”CRC和IBD的不同聚类亚型。然而，遗传病因学 由于先前马赛克研究的局限性，这些病理学的基础是未知的。这项建议会 在健康组织和发病机制的背景下检查结肠镶嵌的时空动力学。 评估整个结肠的镶嵌性将提供对区域特异性 内源性或外源性诱变解释了区域发病机制的变异。 Lee-Six等人的初步研究报告了在所有受试者中突变特征比例的变化。 结肠然而，该分析受限于其低测序覆盖率（~ 15 x）和对小片段的检查。 在一个小的队列中的结肠子区域的数量。利用尸体组织和结肠镜检查 随着生物学和计算技术的进步，我将用更大的 假设检验的分辨率和能力。该提案将确定基于个人和群体的 通过结肠的解剖亚位点的突变率，并提取突变特征， 诱变过程，如细胞增殖或微生物组变异。我假设中肠- 并且后肠衍生的结肠结构将具有来自独特诱变的不同突变特征， 不同区域的突变率。这些突变景观可能会在区域上与 CRC和IBD的空间相关发现，表明在发病机制中的作用。完成本提案将 然后作为一个理想的框架来检查其他组织中的区域变异和发病机制。