Core A: Molecular Pathology Core

核心 A：分子病理学核心

• 批准号: 10218082
• 负责人: Hikmat Al-Ahmadie
• 金额: $ 24.94万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218082
• 关键词: ARID1A gene; Abate; Academic Medical Centers; Address; Bioinformatics; Biological Assay; Biological Models; Biometry; Bladder; Bladder Neoplasm; Cancer Patient; Clinical; Clinical Research; Collaborations; DNA Repair; DNA Sequence Alteration; Disease; Disease Progression; ERCC2 gene; Epigenetic Process; Evaluation; Event; Evolution; Generations; Genetic; Genetically Engineered Mouse; Genitourinary system; Genomics; Goals; Histologic; Human; Human Biology; In Situ Hybridization; Individual; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Memorial Sloan-Kettering Cancer Center; Metastatic to; Methods; Microdissection; Modeling; Molecular; Molecular Analysis; Molecular Biology; Morphology; Mus; Muscle; Mutation; Neoplasm Metastasis; Organoids; Pathogenesis; Pathologist; Pathology; Patients; Play; Population Heterogeneity; Primary Neoplasm; Principal Investigator; Process; Prognostic Marker; Regulator Genes; Research; Research Personnel; Role; Sampling; Specimen; Surgical Pathology; The Cancer Genome Atlas; Time; Tissue Microarray; Tissues; Tumor Biology; Tumor Tissue; Urothelium; Validation; Work; base; biobank; cancer subtypes; chemotherapy; clinical investigation; ethnic diversity; gender diversity; human disease; human model; human tissue; interest; loss of function; molecular pathology; mouse model; muscle invasive bladder cancer; next generation sequencing; novel therapeutic intervention; patient population; pre-clinical; predictive marker; programs; response; tumor

Project Summary/Abstract: The objectives of the Molecular Pathology Core are: (i) to provide Program Project investigators with access to high-quality, clinically-annotated human bladder tumors that represent the full spectrum of the disease, (ii) to assist investigators with acquisition of human bladder tumors for molecular studies and organoid generation, and (iii) to assist with the morphologic, histopathologic, and genomic characterization of bladder tumors, including those that arise in genetically-engineered mouse models (GEMMs). Core A will play a central role in collecting, annotating, storing, and distributing human tissues as required for each Project, and will assist with histologic, molecular, and genomic analyses of murine and human tumors and organoids, and with the validation of molecular findings from model systems to human urothelial cancer. The particular scientific focus of Core A will be to work with Program investigators to pursue analysis of the temporal sequence in which genomic alterations arise in human bladder cancer. The Aims of the Core are: Aim 1: To acquire and maintain a biorepository of urothelial tumors that reflects all states of disease progression from early non- invasive tumors, to muscle-invasive primary tumors to metastatic lesions, and that reflects the ethnic and gender diversity of patients with urothelial tumors. The Core will work with Program investigators to define the temporal sequence of mutational events in bladder cancer, with a focus on the timing of mutations in epigenetic regulators, such as KDM6A and ARID1A, and genes associated with DNA repair and chemotherapy response, such as ERCC2. The Core will also construct tissue microarrays from bladder specimens, particularly those that have been characterized for genomic alterations, to facilitate validation of key molecular findings from studies of GEMMs and human organoid models to human bladder cancer. Aim 2: To provide expert histopathologic evaluation and molecular characterization of bladder tumors from patients and mice. Core A will play a key role in the molecular characterization of mouse and human urothelial tumors by selecting the most representative tumor regions to be analyzed and by performing macro- or microdissection as needed to enrich for tumor content or to separate non-invasive from invasive or morphologically distinct regions. Core A will also assist the Program investigators with genomic sequencing analyses of tumors, as well as with performing and interpreting H&E, immunohistochemical, and in situ hybridization assays. Integration: Each Project will require contribution from the Molecular Pathology Core to achieve their proposed research aims. Project Leaders will work with the Core to obtain and process paired non-invasive/invasive and primary/metastatic samples and samples collected at distinct times in a patient's disease course to define the timing at which genomic alterations arise during bladder cancer pathogenesis. The Core will also assist in the histopathologic morphologic and molecular characterization of GEMMs organoid models.

项目摘要/摘要： 分子病理学核心的目标是：（i）为计划项目调查人员提供 获取代表该疾病的全部光谱的高质量，临床上注销的人膀胱肿瘤， （ii）帮助研究人员获得人膀胱肿瘤进行分子研究和类器官 产生和（iii）有助于膀胱的形态学，组织病理学和基因组表征 肿瘤，包括在遗传工程的小鼠模型（GEMM）中出现的肿瘤。核心A将扮演中央 在收集，注释，存储和分发每个项目所需的人体组织中的作用，并将协助 通过组织学，分子和基因组分析的鼠，人类肿瘤和器官，以及与 从模型系统到人尿路上皮癌的分子发现的验证。特别的科学重点 核心A将是与计划调查员合作，以进行时间顺序分析 人膀​​胱癌发生基因组改变。核心的目的是：目标1：获取和维护 尿路上皮肿瘤的生物措施，反映了从早期非早期疾病进展的所有状态 浸润性肿瘤，肌肉侵入性原发性肿瘤转移性病变，这反映了种族 尿路上皮肿瘤患者的性别多样性。核心将与计划调查人员合作 定义膀胱癌突变事件的时间序列，重点是 表观遗传调节剂，例如KDM6A和ARID1A，以及与DNA修复和化学疗法相关的基因 响应，例如ERCC2。核心还将构建来自膀胱标本的组织微阵列，特别是 那些以基因组改变为特征的，以促进从中验证关键分子发现 对人类膀胱癌的宝石和人体器官模型的研究。目标2：提供专家 来自患者和小鼠的膀胱肿瘤的组织病理学评估和分子表征。 核心A将通过选择小鼠和人尿路上皮肿瘤的分子表征起关键作用 可以根据需要进行宏观或显微解剖的最具代表性的肿瘤区域 富含肿瘤含量或将非侵入性与侵入性或形态上不同的区域分开。核心A。 还将通过基因组测序肿瘤分析以及 执行和解释H＆E，免疫组织化学和原位杂交测定法。 集成：每个项目都需要分子病理核心的贡献才能实现其提议 研究目的。项目负责人将与核心合作，以获取和处理配对的非侵入性/侵入性和 在患者病课程中在不同时间收集的原发性/转移性样本和样本，以定义 在膀胱癌发病机理期间出现基因组改变的时间。核心也将有助于 Gemms类器官模型的组织病理学形态和分子表征。