THE ROLE OF LACTOSYLCERAMIDE IN RENAL AGING AND DISEASE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 肾功能随着年龄的增长而下降，导致许多内科并发症。肾脏疾病的患病率也有所上升。随着老年人口的增加，我们的目标是找出影响肾脏衰老的因素，以开发新的治疗方法来改善老年人的肾功能，并治疗老年相关的肾脏疾病。体外组织培养研究表明，鞘糖脂调节炎症和细胞增殖等细胞过程，这些过程已知在肾脏老化和疾病中发挥作用。然而，目前尚不清楚鞘糖脂在哺乳动物肾脏衰老中是否起到活体作用。我们有令人兴奋的初步数据表明，在衰老过程中，肾脏中特定种类的糖鞘糖脂增加了8倍以上。此外，卡路里限制(CR)是唯一已知的干预措施，可以延长哺乳动物的平均和最长寿命，并在衰老过程中保护肾脏功能，完全防止观察到的老年肾脏中鞘糖脂的升高。综上所述，这些数据使我们提出了以下假设：衰老过程中肾脏鞘脂代谢的改变导致糖鞘糖脂的积聚，而糖鞘脂又至少在一定程度上调节了肾功能的下降；CR阻止了衰老过程中肾脏鞘糖脂的积累，从而减轻了肾功能的下降。这一假设将以两个特定的目标进行检验：(1)确定衰老过程中肾脏鞘糖脂升高的机制、位置和作用；(2)确定CR阻止衰老过程中肾脏鞘糖脂升高的机制。在这项提案中的研究完成后，我们将确立鞘糖脂作为肾脏老化的关键调节因素，并确定开发CR模拟物以保护老年人肾功能的新靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Renal function declines with aging, leading to numerous medical complications. There is also an elevated prevalence of renal disease. As the elderly population is expanding, it is our goal is to identify factors that mediate kidney aging for the development of novel therapeutics to improve renal function in the aged and treat aged-related kidney disease. In vitro tissue culture studies suggest that glycosphingolipids regulate cellular processes such as inflammation and cell proliferation that are known to play roles in kidney aging and disease. However, it is not known if glycosphingolipids play an in vivo role in kidney aging in mammals. We have exciting preliminary data indicating that particular species of glycosphingolipids are elevated more than 8-fold in the kidney during aging. Moreover, caloric restriction (CR), the only known intervention that extends the mean and maximum lifespan in mammals as well as preserves kidney function during aging, completely prevents the observed elevation in glycosphingolipids in the aged kidney. Taken together, these data have led us to propose the following hypothesis: altered renal sphingolipid metabolism during aging leads to accumulation in glycosphingolipids which in turn mediate, at least in part, the decline in kidney function; CR prevents the accumulation of renal glycosphingolipids during aging, thus attenuating the decline in kidney function. This hypothesis will be tested with two specific aims: (1) determine the mechanism, location, and role for elevated renal glycosphingolipids during aging and (2) determine the mechanism by which CR prevents the elevation in renal glycosphingolipids during aging. At the completion of the studies included in this proposal, we will have established glycosphingolipids as key regulators of renal aging and identified novel targets for the development of CR mimetics to preserve kidney function in the elderly.