ROLE OF TGF BETA 1 IN RENAL CANCER

描述（申请人的描述）：肾透明细胞癌（RCC）， 最常见的肾癌，发生在27，000个人在美国， 每年造成11，000人死亡。治疗RCC 仍然令肿瘤学家感到沮丧，局部不值得尊敬和转移 这种疾病的预后很差。 von Hippel-Lindau（VHL）肿瘤抑制因子 基因已被牵连在遗传性和大多数的发病机制 散发性RCC（超过75%）。 申请人有初步数据 转化生长因子β 1（TGF-β 1）是VHL的新靶点， 基因产物（pVHL），并且pVHL降低TGF-β 1 mRNA半衰期。研究 还显示中和抗TGF-β 1抗体抑制皮下 VHL相关的RCC肿瘤在裸鼠中。该提案的前半部分旨在 剖析pVHL调节TGF-β 1的分子机制。 他们将 第一个目的是描绘TGF-β 1 mRNA中对pVHL应答的顺式序列， 然后表征与顺式元件结合的蛋白质。下半年 建议将集中在定义升高的生物学意义上， RCC中的TGF-B1。 申请人将首先定义丧失响应性 体外RCC细胞系对外源性TGF-β 1的敏感性。然后，他们将致力于了解 抗TGF-β_1抗体抑制RCC肿瘤的机制，并确定 TGF-β 1在肿瘤转移中的作用这些有重点的研究形成了一个 了解VHL相关RCC的发病机制， 确定治疗肾细胞癌的新途径。 所描述的工作将在哈佛杰出的环境中进行 医学院和Vikas P. Sukhatme，M.D.的实验室，哲学博士、一个 癌症生物学领域经验丰富的研究人员（WT-1，Egr-1）。新 方法 申请人将学习包括RNA凝胶移位、RNA酶 保护试验，紫外交联，诱变，突变分析，动物 工作和免疫组化。

DESCRIPTION (Applicant's Description): Clear-cell renal carcinoma (RCC), the most common cancer of the kidney, occurs in 27,000 individuals in the US each year and is responsible for 11,000 deaths annually. The treatment of RCC remains frustrating to the oncologist and locally unrespectable and metastatic disease has dismal prognosis. The von Hippel-Lindau (VHL) tumor suppressor gene has been implicated in the pathogenesis of hereditary and in the majority of sporadic RCCs (more than 75 percent). The applicants have preliminary data that transforming growth factor-beta 1 (TGF-B1) is a novel target for the VHL gene product (pVHL) and that pVHL decreases TGF-B1 mRNA half-life. Studies have also shown that neutralizing anti-TGF-B1 antibodies inhibits subcutaneous VHL-associated RCC tumors in nude mice. The first half of the proposal aims to dissect the molecular mechanisms by which pVHL regulates TGF-B1. They will first aim to delineate cis-sequences in the TGF-B1 mRNA responsive to pVHL and then characterize proteins binding to the cis-elements. The second half of the proposal will be focused on defining the biological significance of elevated TGF-B1 in RCCs. The applicants will first define the loss of responsiveness of RCC lines in vitro to exogenous TGF-B1. Then, they will aim to understand the mechanism of RCC tumor inhibition by anti-TGF-B1 antibodies and define the role of TGF-B1 in metastasis. These focused studies form the beginnings of a framework to understand the pathogenesis of VHL-associated RCCs and to identify novel avenues for the treatment of RCC. The work described will be performed in the outstanding environment of Harvard Medical School and in the laboratory of Vikas P. Sukhatme, M.D., Ph.D., an experienced researcher in the field of cancer biology (WT-1, Egr-1). New methodologies the applicant will learn include RNA gel shifts, RNase protection assays, UV crosslinking, mutagenesis, mutation analysis, animal work and immunohistochemistry.