Tubular lysosomes in health and disease

项目摘要 在过去的世纪里，人类的平均寿命急剧增加，然而，健康寿命却没有扩大 相应地此外，神经退行性疾病现在是残疾调整寿命年的主要原因 （DALLS），一个“健康”年损失的量化指标。因此，衰老和与年龄有关的疾病 成为公共卫生的主要问题。为了开始解决这些问题，我们正在使用两个基因 易处理的模型系统，果蝇和C.研究自然衰老过程的机制 以及这些过程如何在晚年出错，引发与年龄有关的疾病。目前，我们有三个 重点领域。首先，我们正在使用CRISPR/Cas9技术来设计人类退行性疾病 在果蝇中建立模型，在分子、细胞和生物体水平上研究疾病病理学。我们是模特 生成还提供了一个强大的时间和成本效益的平台，以筛选潜在的遗传和化学 治疗策略我们的第二个主要研究领域是研究一个新描述的类， 降解的管状溶酶体，其在诱导时表现出有益健康的能力。我们的主要目标是 了解管状溶酶体是如何在某些组织中自然诱导的，并利用这些信息来测试 当在非原生环境中诱导时，它们的促健康作用是否可以被选择来抑制细胞衰老。 我们的第三个主要关注领域是更好地了解睡眠和衰老之间的关系。睡眠减少 通常与许多健康问题和寿命缩短有关;然而，一些天生的短睡眠者 他们能够在不损害整体健康的情况下减少睡眠，在某些情况下甚至活得更长。使用 人类自然短睡眠突变的果蝇模型，我们正在研究自然短睡眠者如何能够 在睡眠减少的情况下保持健康。此外，我们正在探索寿命延长如何影响睡眠; 也就是说，激活促长寿途径是否会降低睡眠压力。总的来说，我们预计 从这些研究中获得的见解将为改善老年人健康的新战略提供信息。

Project summary In the past century, the average human lifespan has increased dramatically; however, healthspan has not scaled accordingly. Moreover, neurodegenerative diseases are now the leading cause for disability adjusted life years (DALYs), a quantitative measure of “healthy” years lost. Therefore, aging, and age-related diseases have become major public health concerns. To begin addressing these concerns, we are using two genetically tractable model systems, Drosophila and C. elegans, to study mechanisms governing the natural aging process and how these processes may go awry during late age to trigger age-related diseases. Currently, we have three major areas of focus. First, we are using CRISPR/Cas9 technology to engineer human degenerative disease models in flies to study the disease pathology at a molecular, cellular, and organismal level. The models we are generating also provide a robust time- and cost-effective platform to screen potential genetic and chemical therapeutic strategies. Our second major research area is focused on studying a newly described class of degradative tubular lysosomes that exhibit pro-health capabilities when induced. Our major goal is to better understand how tubular lysosomes are induced in certain tissues naturally and utilize this information to test whether their pro-health effects can be co-opted to suppress cellular aging when induced in non-native contexts. Our third major area of focus is to better understand the relationship between sleep and aging. Reduced sleep is typically associated with many health issues and reduced lifespan; however, some natural short sleepers are able to sleep less without compromising their overall health and, in some cases, even live longer. Using a Drosophila model of a human natural short sleep mutation, we are studying how natural short sleepers are able to maintain health despite sleeping less. Further, we are exploring how increasing longevity affects sleep; namely, whether activating pro-longevity pathways reduces sleep pressure. Collectively, we anticipate that the insights from these studies will inform new strategies to improve late-age health.