Molecular Systems Pathology Core

分子系统病理学核心

• 批准号: 8555290
• 负责人: CARLOS CORDON-CARDO
• 金额: $ 18.05万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555290
• 关键词: Abate; Androgens; Area; Biological Assay; Biological Markers; Clinical; Communities; DNA Damage; Data; Databases; Development; Diagnostic Neoplasm Staging; Enrollment; Epithelial; Evaluation; Event; Fluorescent in Situ Hybridization; Fresh Tissue; Gene Expression; Generations; Genes; Genetic; Genitourinary system; Gleason Grade for Prostate Cancer; Goals; Guidelines; Histopathology; Human; Image Analysis; In Situ Hybridization; Interphase; Laboratory Study; Lesion; Letters; Link; Malignant neoplasm of prostate; Maps; Memorial Sloan-Kettering Cancer Center; Mission; Molecular; Mus; Mutation; NKX3-1 gene; Oncology Group; Operative Surgical Procedures; Pathology; Pathway interactions; Patients; Pattern; Process; Prostate; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Research Personnel; Resolution; Resources; Sampling; Services; Southwest Oncology Group; Specimen; Stem cells; System; TMPRSS2 gene; Technical Expertise; Tissue Microarray; Tissues; Training; Translational Research; Tumor stage; Validation; Work; cancer initiation; clinically significant; cohort; design; innovation; morphometry; mouse model; neoplastic; new technology; novel; novel marker; progenitor; programs; response marker; senescence; stem; technology development; tissue resource; tumor; tumor progression; tumorigenesis

The Molecular Systems Pathology Core will provide expert morphological evaluation of normal and tumor samples of human and mouse models to investigators of the Program Project. The Core will further develop novel technology in the areas of morphometry and image analysis of quantitative biomarker multiplexing in tissue sections. This Core is also generating new assays, such as those for analysis of DNA damage using H2AX quantitation at high spectral resolution, for studying senescence at the microanatomical detail, and ex vivo assays using fresh human prostate cancer specimens. Through such approaches, the Core will integrate with all three Projects in pursuing systems pathology approaches to investigate expression of NKX3.I (the major scientific goal of the Core), to study markers of prostate stem cells (Project 1), to examine the expression of direct transcriptional targets of NKX3.1 (Project 2), and to quantify DNA damage response markers in human and mouse prostate tissues (Project 3). We have ample tissue resources to assist all Projects, including a set of 140 human prostate tumors (training set), a second independent cohort of 410 human prostate tumors (validation set), as well as large and well characterized cohorts of human prostate cancer tissues from Memorial Sloan-Kettering Cancer Center (MSKCC) and the Genitourinary Program of the Southwestern Oncology Group (GU-SWOG). This Core also provides assistance in conducting immunohistochemical (IHC) and in situ hybridization (ISH) assays, including interphase fluorescence in situ hybridization (FISH). Using these resources, we will characterize expression patterns of known genes participating in pathways of relevance for the Program, as well as novel genes identified through studies conducted by the proposed projects. The specific aims are: (1) To investigate the occurrence and correlation of molecular alterations associated with prostate cancer initiation in human preneoplastic and tumor lesions, an aim that includes both technology development and further definition of the temporal map of molecular alterations associated with prostate cancer progression; (2) To examine the expression of NKX3.1 and stem/progenitor markers in androgen-ablated and hormonally-intact human prostate specimens, working with Michael Shen in Project 1; (3) To characterize the expression of NKX3.1 and its transcriptional targets identified in Project 2 using normal and tumor human specimens, working with Cory Abate-Shen; and (4) To further study the relationship of NKX3.I inactivation and the formation of TMPRSS2-ERG fusions, studying pre- and post-treated mice after DNA damage with Edward Gelmann in Project 3.

分子系统病理学核心将为该计划的研究人员提供人类和小鼠模型的正常和肿瘤样本的专家形态学评估。该核心将进一步开发组织切片中定量生物标志物多重形态测量和图像分析领域的新技术。该核心还产生了新的检测方法，例如使用高光谱分辨率的 H2AX 定量分析 DNA 损伤的方法、用于研究微观解剖细节的衰老的方法，以及使用新鲜人类前列腺癌样本进行的离体检测方法。通过这些方法，核心将与所有三个项目整合，追求系统病理学方法，以研究 NKX3.I 的表达（核心的主要科学目标），研究前列腺干细胞的标记（项目 1），检查 NKX3.1 直接转录靶标的表达（项目 2），并量化人类和小鼠前列腺组织中的 DNA 损伤反应标记（项目 3）。我们拥有充足的组织资源来协助所有项目，包括一组 140 个人类前列腺肿瘤（训练集）、第二个独立队列（包含 410 个人类前列腺肿瘤）（验证集），以及来自纪念斯隆-凯特琳癌症中心 (MSKCC) 和西南肿瘤学组泌尿生殖计划 (GU-SWOG) 的大型且特征明确的人类前列腺癌组织队列。该核心还为进行免疫组织化学 (IHC) 和原位杂交 (ISH) 检测提供帮助，包括间期荧光原位杂交 (FISH)。利用这些资源，我们将描述参与该计划相关途径的已知基因的表达模式，以及通过拟议项目进行的研究确定的新基因。具体目标是：（1）研究人类癌前和肿瘤病变中与前列腺癌发生相关的分子改变的发生和相关性，该目标包括技术开发和进一步定义与前列腺癌进展相关的分子改变的时间图； (2) 与项目 1 中的 Michael Shen 合作，检查雄激素去除和激素完整的人类前列腺标本中 NKX3.1 和干细胞/祖细胞标记的表达； (3) 与 Cory Abate-Shen 合作，使用正常和肿瘤人类标本来表征项目 2 中确定的 NKX3.1 及其转录靶标的表达； (4) 进一步研究NKX3.I失活与TMPRSS2-ERG融合体形成的关系，在项目3中与Edward Gelmann一起研究DNA损伤后治疗前和治疗后的小鼠。