THE ROLE OF LACTOSYLCERAMIDE IN RENAL AGING AND DISEASE

乳糖神经酰胺在肾脏衰老和疾病中的作用

• 批准号: 8360388
• 负责人: LEAH J SISKIND
• 金额: $ 10.84万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-07-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360388
• 关键词: Aging; Attenuated; Caloric Restriction; Cell Proliferation; Cell physiology; Centers of Research Excellence; Data; Development; Disease; Elderly; Funding; Glycosphingolipids; Goals; Grant; In Vitro; Inflammation; Intervention; Kidney; Kidney Diseases; Lactosylceramides; Location; Longevity; Mammals; Mediating; Metabolism; National Center for Research Resources; Play; Population; Prevalence; Principal Investigator; Renal function; Research; Research Infrastructure; Resources; Role; Source; Sphingolipids; Testing; United States National Institutes of Health; age related; aged; cost; improved; in vivo; medical complication; mimetics; novel; novel therapeutics; prevent; tissue culture

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 随着年龄的增长，肾功能下降，导致许多医疗并发症。肾脏疾病的患病率也有所上升。随着老年人口的不断扩大，我们的目标是确定介导肾脏衰老的因素，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性肾脏疾病。体外组织培养研究表明，鞘糖脂调节细胞过程，如炎症和细胞增殖，已知在肾脏衰老和疾病中发挥作用。然而，目前尚不清楚鞘糖脂是否在哺乳动物肾脏衰老中发挥体内作用。我们有令人兴奋的初步数据表明，在衰老过程中，肾脏中特定种类的鞘糖脂升高超过8倍。此外，热量限制（CR）是唯一已知的可以延长哺乳动物平均和最大寿命并在衰老过程中保留肾功能的干预措施，可以完全防止老年肾脏中观察到的鞘糖脂升高。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鞘糖脂蓄积，进而至少部分介导肾功能下降; CR可防止衰老过程中肾脏鞘糖脂蓄积，从而减轻肾功能下降。该假设将通过两个特定目的进行检验：（1）确定衰老过程中肾鞘糖脂升高的机制、位置和作用;（2）确定CR预防衰老过程中肾鞘糖脂升高的机制。在完成本提案中包含的研究时，我们将确定鞘糖脂作为肾老化的关键调节因子，并确定开发CR模拟物以保护老年人肾功能的新靶点。