Chromatin Regulation by Mammalian SIRT7 in Aging and Disease

衰老是许多慢性病的最大风险因素，因此是导致慢性病的主要因素。 VA人群的发病率。我们广泛的研究目标是了解染色质如何调节 机制影响核和表观遗传程序，以及如何解除这些机制的管制 会导致衰老和疾病本文提出的工作将集中在阐明SIRT 7的功能， 衰老调节因子Sirtuin家族中的一种染色质调节酶。小鼠中SIRT 7的失活 导致寿命缩短和与衰老、癌症和代谢紊乱相关的表型。因此，在本发明中， 研究SIRT 7的分子机制和生理功能有望阐明SIRT 7的中枢神经系统功能。 影响衰老和健康寿命的分子途径。 该项目将研究SIRT 7在防止基因组不稳定性方面的新机制， 细胞衰老，与年龄相关疾病有关的基本衰老机制， 是组织功能障碍的重要原因。最近的研究表明，消除衰老细胞， 可以预防或逆转从癌症到脂肪肝等一系列与衰老相关的疾病。 通过阐明控制细胞衰老的SIRT 7信号通路，所提出的工作可以 为制定影响退伍军人健康的衰老相关疾病的治疗策略提供见解。 健康 这项研究的中心假设是，重复核糖体DNA的基因组不稳定性， （rDNA）序列是哺乳动物细胞衰老的驱动因素，SIRT 7可以防止衰老。 这种不稳定性通过维持rDNA染色质沉默通过新的机制。分子，细胞， 和遗传学的方法将被用来（1）研究的分子机制和生物背景， SIRT 7在控制rDNA染色质动力学中的作用;（2）阐明SIRT 7与一种新的 描述了在许多癌症中突变的rDNA沉默途径;和（3）表征下游 SIRT 7在rDNA序列上的染色质信号传导机制。 越来越多的证据表明，rDNA不稳定性可能是许多癌症的致癌驱动因素， 衰老细胞可在肿瘤恶性和无数与衰老相关的病理中具有致病作用。 通过阐明控制rDNA不稳定性和细胞衰老的SIRT 7信号通路， 拟议的工作可以为开发衰老相关疾病的治疗策略提供见解， 影响退伍军人的健康。

Aging is the single greatest risk factor for many chronic diseases and thus is a major contributor to morbidity in the VA population. Our broad research goal is to understand how chromatin regulatory mechanisms influence nuclear and epigenetic programs, and how de-regulation of these mechanisms contributes to aging and disease. The work proposed here will focus on elucidating the functions of SIRT7, a chromatin regulatory enzyme in the Sirtuin family of aging-regulatory factors. Inactivation of SIRT7 in mice leads to shortened lifespan and phenotypes associated with aging, cancer, and metabolic disorders. Thus, studying the molecular mechanisms and physiologic functions of SIRT7 promises to elucidate central molecular pathways that impact on aging and health span. This project will study novel mechanisms of SIRT7 in protecting against genomic instability and cellular senescence, fundamental aging mechanisms that are implicated in age-related diseases and are a significant cause of tissue dysfunction. Recent studies indicate that elimination of senescent cells in mice can prevent or reverse a wide range of aging-related pathologies, from cancer to fatty liver disease. By elucidating the SIRT7 signaling pathways that control cellular senescence, the proposed work can provide insights for developing therapeutic strategies for aging-related diseases that impact Veterans' health. The central hypothesis of the study is that genomic instability at repetitive ribosomal DNA (rDNA) sequences is a driver of senescence in mammalian cells, and that SIRT7 guards against such instability by maintaining rDNA chromatin silencing via novel mechanisms. Molecular, cellular, and genetic approaches will be taken to (1) study the molecular mechanisms and biological contexts of SIRT7 in controlling rDNA chromatin dynamics; (2) elucidate the functional interplay of SIRT7 with a newly described rDNA silencing pathway that is mutated in numerous cancers; and (3) characterize downstream chromatin signaling mechanisms of SIRT7 at rDNA sequences. Accumulating evidence indicates that rDNA instability may be an oncogenic driver in many cancers, and senescent cells can have pathogenic effects in tumor malignancy and myriad aging-associated pathologies. By elucidating the SIRT7 signaling pathways that control rDNA instability and cellular senescence, our proposed work can provide insights for developing therapeutic strategies for aging-related diseases that impact Veterans' health.