MONOCLONAL ANTIBODIES TO TELOMERE ASSOCIATED PROTEINS

端粒酶是一种催化染色体末端短端粒重复序列(TTAGGG)n替换从而维持端粒长度的酶。端粒DNA的缺失会导致细胞衰老，而端粒酶活性过强则会导致细胞永生。端粒酶现在被确定为癌症的敏感和特异的标记物。在各种肿瘤中，端粒酶活性也被证明可以作为检测癌前组织或早期恶性肿瘤的标志，也可以用于预测患者的生存。随着端粒酶基因/S(TRT/EST2和TPI)的克隆，现在有可能开发出用于临床实验室的简单、快速的基于抗体的癌症诊断方法。最近，TRF1、TRF2和tankyrase等通过不同机制调节端粒长度的其他关键因子也被克隆出来。在这项可行性研究中，我们建议开发针对TRT、TP1、TRF1、TRF2和tankyrase的高度特异的单抗。通过使用细胞系/组织模型，我们将评估它们在癌症诊断中的作用。在我们的第二阶段计划中，选定的试剂小组将针对大量患者肿瘤进行广泛测试，以测试这些因子的表达模式是否与早期恶性肿瘤有关。建议的商业应用：目前，还没有针对端粒酶和端粒相关因子的单抗。由于这一领域目前是深入研究的主题，端粒酶抗体和其他端粒相关因子不仅在研究中有用处，而且在诊断癌症和癌前状态以及监测治疗方面也有用处。

Telomerase is an enzyme that catalyzes the replacement of short telomeric repeats (TTAGGG)n at the ends of chromosomes and thus maintains the length of telomeres. Loss of telomeric DNA results in senescence whereas strong telomerase activity results in cell immortality. Telomerase Is now established as a sensitive and specific marker for cancer. In various neoplasms1 it has also been shown that telomerase activity may be used as a marker for detecting pre-cancerous tissue or early stage of malignancy and may also be used for predicting patient survival. with the cloning of the telomerase gene/s (TRT/EST2 and TPI) it is now possible to develop simple and rapid antibody based methods for cancer diagnosis for use in clinical laboratories. Recently, other key factors including TRF1, TRF2 and Tankyrase that regulate telomere length through distinct mechanisms have been cloned. In this feasibility study, we propose to develop highly specific monoclonal antibodies to TRT, TP1, TRF1, TRF2 and Tankyrase. Through the use of cell line/tissue models we will evaluate their utility for diagnosis of cancers. In our Phase II proposal, the selected panel of reagents will be tested extensively against a large number of patient tumors to test whether patterns of expression of these factors may be related with early stages of malignancy. PROPOSED COMMERCIAL APPLICATIONS: Presently, there are no monoclonal antibodies to telomerase and telomer associated factors. As this area is presently the subject of intensive study, antibodies to telomerase and other telomere--associated factors will have utility not only in research, but also in diagnosing cancers and pre- cancerous states and monitoring therapy.