Telomerase in Development Senescence and Neoplasia

描述(申请人提供)：端粒功能障碍是衰老、退行性疾病和癌症的主要决定因素。在癌症中，端粒和端粒酶已被证明在恶性肿瘤的发生和发展中发挥关键作用。端粒功能障碍，加上失活的P53检查点，使基因组不稳定和癌症的发展和进展，包括转移。在目前的资助中，重要的工作是阐明p53依赖的端粒检查点反应的连接以及p53下游靶点如何促进退行性疾病和恶性进展。在我们正在进行的工作的基础上，这次更新将涉及两个重要的研究领域。第一个领域集中在P53途径的两个关键靶点。从我的实验室从目前的资助期开始的工作已经发现，在端粒功能障碍的小鼠中，线粒体的生物发生和功能存在着严重的缺陷，这是由于P53直接抑制转录共激活因子PGC11/2，PgC11/2是线粒体生物发生的主要调节因子，以及P53直接激活Quking(QK)，QK是一种RNA结合蛋白，我们证明它是一种有效的肿瘤抑制因子，也是microRNA直接控制关键线粒体调节因子PPARa的调节器。这些观察结果导致了一种假设，即线粒体病变和相关的能量损失是端粒功能障碍小鼠年龄相关疾病的主要原因，并可能决定癌细胞的某些代谢反应。这一竞争性更新的目标将是从遗传学角度评估衰老和癌症中的端粒-线粒体联系。具体工作集中在(I)利用可诱导端粒酶模型(TERT-ER)来评估端粒再生对线粒体生物学以及干细胞和多种有丝分裂后器官系统的退变表型的影响；(Ii)从遗传学上确定PGC11/2和QK靶标作为端粒检查点反应的关键介质在线粒体生物学、退行性衰老以及癌症和癌症基因组变化的发生和发展中的重要性。第二个领域涉及到抗端粒酶治疗概念的翻译。我们以前的工作表明，抗端粒酶治疗应该优先避免P53缺失的肿瘤患者。在这次更新中，我们将验证端粒酶消退作为抗癌治疗的原理，并在基因组和代谢水平上确定抗端粒酶治疗的潜在耐药机制。这些机制的确定将导致可能与抗端粒酶治疗协同作用的新药的出现。 公共卫生相关性： 端粒功能障碍是衰老、退行性疾病和癌症的标志之一。我们将验证端粒酶消退作为抗癌治疗的原理，并确定潜在的耐药机制，这些机制将导致可能与抗端粒酶治疗协同的新药。

DESCRIPTION (provided by applicant): Telomere dysfunction is a major determinant of aging, degenerative diseases and cancer. In cancer, the telomeres and telomerase have been shown to play critical roles in the initiation and progression of malignancy. Telomere dysfunction, coupled with deactivated p53 checkpoints, enables genome instability and the development and progression of cancer, including metastasis. Significant effort in the current grant has been elucidating the wiring of the p53-dependent telomere checkpoint response and how p53 downstream targets promote degenerative conditions and enable malignant progression. Building on our ongoing work, this renewal will address two important areas of study. First area focuses on two critical targets of the p53 pathway. Work from current funding period from my laboratory has identified a profound deficiency in mitochondria biogenesis and function in telomere dysfunctional mice which results from p53-directed repression of PGC11/2 transcriptional coactivators, the master regulators of mitochondrial biogenesis and p53-directed activation of Quaking (QK), a RNA binding protein which we show is a potent tumor suppressor and regulator of microRNA-directed control of the key mitochondrial regulator, PPARa. These observations have led to the hypothesis that mitochondriopathy and associated energy loss is the primary cause of age related maladies in telomere dysfunctional mice and may dictate certain metabolic responses in cancer cells. The objectives of this competitive renewal will be to genetically assess the telomere-mitochondria link in aging and cancer. The specific efforts focus on (i) the use of an inducible telomerase model (TERT-ER) to assess the regenerative impact on mitochondrial biology and degenerative phenotypes in stem cells and diverse post-mitotic organ systems in aged telomere dysfunction mice; (ii) to genetically define the importance of the PGC11/2 and QK targets as critical mediators of the telomere checkpoint response with respect to mitochondria biology, degenerative aging, and the genesis and progression of cancer and cancer genomic changes. Second area speaks to translation of the concept of anti-telomerase therapy. Our previous work has suggested that anti-telomerase therapy should preferentially avoid patients with p53-deficient tumors. In this renewal, we will validate the principal of telomerase extinction as an anti-cancer therapy and define potential resistance mechanisms on the genomic and metabolic levels to anti-telomerase therapy. The identification of these mechanisms should lead to new drugs that may synergize with anti-telomerase therapy. PUBLIC HEALTH RELEVANCE: Telomere dysfunction is one of the hallmark of aging, degenerative diseases and cancer. We will validate the principal of telomerase extinction as an anti-cancer therapy and define potential resistance mechanisms which should lead to new drugs that may synergize with anti-telomerase therapy.