Ceramide and acute phase proteins elevation during aging
衰老过程中神经酰胺和急性期蛋白升高
基本信息
- 批准号:6607625
- 负责人:
- 金额:$ 25.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-08-01 至 2007-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Aging is associated with chronic sub-clinical inflammation that underlies the increased risk of atherosclerosis and cardiovascular disease. It is manifested by chronic low-amplitude increases in the plasma levels of the major acute phase proteins, such as C reactive protein (CRP), serum amyloid A (SAA) and alpha1 acid glycoprotein (AGP) in the elderly. The long term objective of the proposed research is to deepen our understanding for the relationship between aging, chronic inflammation and regulation of the acute phase proteins. We recently found that ceramide, a second messenger molecule that mediates the acute stimulation of CRP, AGP and SAA during inflammation is chronically increased in liver from old rats and mice. We hypothesize that increased level of ceramide in aging cause chronic activation of C/EBP transcription factor and increased expression of CRP, AGP and SAA. Our objectives are to decipher the role of ceramide increases in aging - associated increase(s) in the expression of APP and to determine to what extent this is similar to the mechanisms that regulate the inflammation-induced changes in APP secretion. We propose the following specific aims: (I) To identify which pathway for ceramide generation leads to induction of acute phase proteins (APP) mRNA increases. Using adenovirus-mediated gene transfer we will overexpress acid and neutral SMases in primary mouse hepatocytes and will test which of the enzymes is sufficient to up-regulate the level of mRNA for three of the major APP in mouse, SAP, AGP and SAA. To identify the subcellular pool of ceramide involved in signaling, subcellular localization of overexpressed ASMase and NSMase will be studied and compared to the localization of the excess ceramide generated during aging and inflammation (2) To test in vitro whether active ASMase or NSMase is required for the induction of APP mRNA by aging and inflammation. In this specific aim we will identify the mechanism for generation of ceramide and induction of APP expression during inflammation and aging. Using hepatocytes from ASMase(-/-) mice and specific inhibitors of NSMase, we will identify which of SMases is indispensable for APP up-regulation. (3) To decipher the role of acid and neutral SMase in APP regulation in vivo. Using acid sphingomyelinase knockout mice, we will validate the conclusions drawn from Sp. Aim 1 and 2 in a physiological context.
The results of these studies will elucidate the factors that regulate ceramide level in inflammation and during aging. An understanding of the cellular and molecular mechanisms responsible for this regulation will help to define how ceramide exerts its effects and its role in cardiovascular disease, atherosclerosis and, perhaps other diseases of the elderly, such as stroke and Alzheimer disease.
描述(由申请人提供):衰老与慢性亚临床炎症相关,慢性亚临床炎症是动脉粥样硬化和心血管疾病风险增加的基础。其表现为老年人中主要急性时相蛋白如C反应蛋白(CRP)、血清淀粉样蛋白A(SAA)和α 1酸性糖蛋白(AGP)的血浆水平的慢性低幅度增加。这项研究的长期目标是加深我们对衰老、慢性炎症和急性期蛋白调节之间关系的理解。我们最近发现,神经酰胺,第二信使分子,介导急性刺激CRP,AGP和SAA在炎症过程中是慢性增加的肝脏从老年大鼠和小鼠。我们推测衰老过程中神经酰胺水平的增加导致C/EBP转录因子的慢性激活以及CRP、AGP和SAA表达的增加。我们的目标是解读神经酰胺增加在APP表达的老化相关增加中的作用,并确定这在多大程度上与调节炎症诱导的APP分泌变化的机制相似。我们提出了以下具体目标:(I)确定神经酰胺产生的途径导致诱导急性期蛋白(APP)mRNA的增加。使用腺病毒介导的基因转移,我们将在原代小鼠肝细胞中过表达酸性和中性SMases,并将测试哪种酶足以上调小鼠中三种主要APP(SAP、AGP和SAA)的mRNA水平。为了鉴定参与信号传导的神经酰胺的亚细胞库,将研究过表达的ASMase和NSMase的亚细胞定位,并与衰老和炎症期间产生的过量神经酰胺的定位进行比较(2)为了体外测试是否需要活性ASMase或NSMase来诱导衰老和炎症引起的APP mRNA。在这一特定目标中,我们将确定炎症和衰老过程中神经酰胺生成和APP表达诱导的机制。使用来自ASMase(-/-)小鼠的肝细胞和NSMase的特异性抑制剂,我们将鉴定哪种SMase对于APP上调是必不可少的。(3)阐明酸性和中性SMase在体内APP调节中的作用。使用酸性鞘磷脂酶基因敲除小鼠,我们将验证的结论从SP。目的1和2在生理背景下。
这些研究的结果将阐明炎症和衰老过程中调节神经酰胺水平的因素。了解负责这种调节的细胞和分子机制将有助于确定神经酰胺如何发挥其作用及其在心血管疾病,动脉粥样硬化和老年人的其他疾病,如中风和阿尔茨海默病中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Mariana N Nikolova-Karakashian其他文献
Mariana N Nikolova-Karakashian的其他文献
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{{ truncateString('Mariana N Nikolova-Karakashian', 18)}}的其他基金
Signaling and metabolic functions of nSMase-2 in hepatic steatosis and onset of insulin resistance
nSMase-2 在肝脂肪变性和胰岛素抵抗发作中的信号传导和代谢功能
- 批准号:
10735117 - 财政年份:2023
- 资助金额:
$ 25.12万 - 项目类别:
Ceramide and acute phase protein elevation during aging
衰老过程中神经酰胺和急性期蛋白升高
- 批准号:
8131944 - 财政年份:2002
- 资助金额:
$ 25.12万 - 项目类别:
Ceramide and acute phase protein elevation during aging
衰老过程中神经酰胺和急性期蛋白升高
- 批准号:
8505322 - 财政年份:2002
- 资助金额:
$ 25.12万 - 项目类别:
Ceramide and acute phase proteins elevation during aging
衰老过程中神经酰胺和急性期蛋白升高
- 批准号:
6543418 - 财政年份:2002
- 资助金额:
$ 25.12万 - 项目类别:
Ceramide and acute phase protein elevation during aging
衰老过程中神经酰胺和急性期蛋白升高
- 批准号:
8309135 - 财政年份:2002
- 资助金额:
$ 25.12万 - 项目类别:
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