PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

中间终点的临床前评估

• 批准号: 2600917
• 负责人: MING YOU
• 金额: $ 41.11万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-30 至 1999-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2600917
• 关键词: RNA; albino mouse; benzanthracenes; breast neoplasms; chemical carcinogenesis; chemoprevention; disease /disorder model; gene expression; gene mutation; human genetic material tag; laboratory rat; lung neoplasms; methylnitrosourea; molecular cloning; neoplasm /cancer genetics; oncogenes; radiation carcinogenesis

Altered Genes Expression In Rat Mammary And Mouse Lung Models: Comparison With Altered Expression In Humans And Modulation of Gene Expression by Known Chemopreventive Agents. Substantial genetic instability, as reflected in LOH or aneuploidy, appear to be a hallmark of most human cancers and even many preinvasive lesions, e.g. DCIS in breast, dysplastic lesions in lung, colon adenomas, CIN 2 and CIN 3 in cervix etc. In contrast a more limited number of oncogenes or tumor suppressor genes [P53, Ki Ras, APC, Rb etc] have been fully characterized for possible mutations and most cancers are characterized for a limited number of mutations in these same genes. The objective of this study is to use methodologies which allow the simultaneous examination of altered RNA levels in hundreds of genes simultaneously and which additionally allows one to clone and perform partial sequencing of the cDNAs coding for these genes in a relatively easy manner. The rat mammary tumor model is being used to readily determine whether effective chemopreventive agents alter levels of the presumptive RNAs identified in the screening mode. 1) Extensive screening of MNU rat mammary tumors for altered expression of various RNAs 2) Compare using a more limited subset of RNAs (40-50) altered expression of these genes in rat mammary tumors induced by MNU, DMBA and tumors induced by radiation plus estradiol 3) Determine again employing a limited number of RNAs whether one sees a substantially different pattern in MNU induced tumors bearing a mutation in the HaRas oncogeny versus those tumors not bearing a mutation in the HaRas oncogene 4) Determine employing a subset of RNAs whether the expression of these genes is modulated by known chemopreventive agents.

大鼠乳腺和小鼠肺模型中基因表达改变的比较 在人类中的表达改变和基因表达的调节 已知的化学预防剂。 基因不稳定，如 反映在洛缺失或非整倍体中，似乎是大多数人类的标志。 癌症，甚至许多浸润前病变，例如乳腺DCIS，发育异常 肺内病变、结肠腺瘤、宫颈CIN 2、CIN 3等 与数量有限的癌基因或肿瘤抑制基因相比， [P53，Ki Ras，APC，Rb等]已被充分表征， 突变和大多数癌症的特征在于有限数量的 这些相同基因的突变。 本研究的目的是利用 允许同时检查改变的RNA的方法 在数百个基因的水平，同时，这还允许 一个用于克隆和进行编码这些的cDNA的部分测序， 基因相对容易。 大鼠乳腺肿瘤模型 用于容易地确定有效的化学预防剂是否改变 在筛选模式中鉴定的推定RNA的水平。 第一章 广泛筛选MNU大鼠乳腺肿瘤的表达改变 2）使用更有限的RNA子集进行比较（40-50） 这些基因在MNU诱导的大鼠乳腺肿瘤中的表达改变， DMBA与辐射加雌二醇诱发的肿瘤 使用有限数量的RNA，无论人们看到的是一个基本上 MNU诱导的携带HaRas突变的肿瘤中的不同模式 致癌性与不携带HaRas癌基因突变的肿瘤 4)确定使用RNA的子集是否表达这些 基因受已知的化学预防剂调节。