A Bioorthogonal Approach to Study Mammalian Aging

 描述(由申请人提供)：年龄是美国大多数主要死亡原因的主要风险因素，包括心脏病、癌症、中风和痴呆症。随着人口迅速老龄化，我们的医疗保健系统已经超出了可承受的范围，公众、资助机构和工业界对老龄化和长寿产生了前所未有的兴趣。我认为，基于化学生物学的巨大技术进步和我们团队提出的部分经验发现，现在是时候问一些关于衰老的基本问题了：是什么控制了生物的衰老？它是否开始于一种组织，然后扩散到另一种组织？或者衰老开始于一种细胞类型，例如干细胞或衰老细胞，然后扩散到其他细胞和组织？或者，它是不是在所有细胞中同时开始，由老化的线粒体驱动，由于DNA或蛋白质维持失败，或其他机制？这项拟议的研究将试图解决这些问题，并遵循我们的开创性发现，即血浆中的可溶性、热不稳定因子足以加速脑胶原或使老化的大脑再生和年轻。这些和其他人关于异慢性异型共生的研究为我的提议提供了基础，证明了可溶性因子携带着关于生物体生物年龄的信息，可溶性因子可以积极地调节衰老，并且衰老是可塑性的，并且可能是可逆的。我将利用化学生物学的非凡发展，允许将遗传编码的非规范氨基酸正交(即独立，不会造成干扰)引入生物体内，并随后检测它们所结合的蛋白质。这一革命性的概念是基于一种重新连接的翻译，在这种翻译中，遗传密码被扩展，从而产生可以化学识别的修饰蛋白质。我们将使用这项技术生产转基因小鼠

 DESCRIPTION (provided by applicant): Age is the major risk factor for a majority of the leading causes of death in the US including heart disease, cancer, stroke, and dementia. With a rapidly aging population pushing the boundaries of what our health care system can absorb, there has been an unprecedented interest in aging and longevity from the public, funding bodies, and industry. I believe that based on dramatic technological advances in chemical biology and empirical findings advanced in part by our group, the time is right to ask some of the fundamental questions about aging: what controls organismal aging? Does it start in one tissue and spread to another? Or does aging start in one cell type, such as in stem cells or senescent cells, and spread to other cells and tissues? Or does it start simultaneously in all cells, driven y aging mitochondria, by failures in DNA or protein maintenance, or other mechanisms? The proposed research will try to address these questions and follows from our groundbreaking discovery that soluble, heat labile factors in blood plasma are sufficient to accelerate brain agin or regenerate and rejuvenate old brains. These and studies with heterochronic parabiosis by others provide the foundation for my proposal by demonstrating that soluble factors carry information about the biological age of an organism, that soluble factors can actively modulate aging, and that aging is malleable and possibly reversible. I will take advantage of the extraordinary developments in chemical biology, which allow for the orthogonal (i.e. independent, causing no interference) introduction of genetically encoded, non-canonical amino acids into living organisms and the subsequent detection of the proteins into which they are incorporated. This revolutionary concept is based on a rewired translation in which the genetic code is expanded resulting in the production of modified proteins, which can be chemically identified. We will generate transgenic mice using this technol