MECHANISMS OF PROSTATE EPITHELIAL CELL TRANSFORMATION

描述：这项提案的总体目标是确定 成人非肿瘤性前列腺的分子遗传学机制 上皮细胞被驱使向越来越恶性的表型发展。 发现与特定细胞遗传学改变相关的研究 SV40大T抗原的致瘤或转移能力 永生化人前列腺上皮细胞(SV40T PEC)裸体培养 MICE为研究转化机制提供了新的途径。在这 提议，需要检验的假设是16号和/或19号染色体 包含一个或多个抑制致瘤性和/或转移的基因。 具体目标是：(1)进一步划定最小损失区域 发生在16号和19号染色体上的杂合性(LOH) 进展；(2)确定是否恢复正常的染色体剂量 通过微细胞介导的转移：(A)完整的正常人类染色体 16，或(B)将19号染色体插入适当的克隆中，将抑制肿瘤 裸鼠的发病率、生长率和/或转移； 利用他们独特的系统来识别16号染色体上的最小区域 和/或19个具有功能性肿瘤抑制活性的基因。这些研究 将有助于了解发生在 美国男人。这可能会带来改善诊断的新机会， 对一种疾病的预后评估或治疗干预 令人满意的治疗选择。

DESCRIPTION: The overall objective of this proposal is to identify molecular genetic mechanisms by which adult human non-neoplastic prostate epithelial cells are driven towards increasingly malignant phenotypes. Investigation of specific cytogenetic alterations found to be associated with the tumorigenic or metastatic capacity of SV40 large T antigen immortalized human prostate epithelial cells (SV40T PEC) in athymic nude mice provides a novel way to study mechanism of transformation. In this proposal, the hypothesis to be tested is that chromosomes 16 and/or 19 contain one or more genes that suppress tumorigenicity and/or metastasis. The specific aims are: (1) to further delineate the minimal regions of loss of heterozygosity (LOH) occurring on chromosomes 16 and 19 as these cells progress; (2) to determine whether restoration of normal chromosome dosage by microcell mediated transfer of: (a) an intact normal human chromosome 16, or (b) chromosome 19 into appropriate clones will suppress tumor incidence, growth rate, and/or metastasis in athymic nude mice; (3) to exploit their unique system to identify the smallest areas on chromosomes 16 and/or 19 that harbor functional tumor suppressor activity. These studies will facilitate understanding of the most common tumor occurring among American men. This may lead to new opportunities for improved diagnosis, prognostic assessment, or therapeutic intervention for a disease having no satisfactory treatment options.