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
• 负责人: Mariana N Nikolova-Karakashian
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309135
• 关键词: Acute-Phase Proteins; Adenoviruses; Affect; Aging; Aging-Related Process; American; Animals; Arthritis; Attenuated; Binding; Biological Assay; Caloric Restriction; Cell membrane; Cells; Cellular Stress Response; Ceramides; Chronic; Complement; Disease; Dose; EMSA; Effectiveness; Elderly; Environment; Event; Exhibits; Funding; Gene Transfer; Genetic Transcription; Glucose; Goals; Health; Hepatic; Hepatocyte; IGF1 gene; Immune response; Impairment; In Vitro; Indium; Inflammation; Inflammatory; Insulin; Insulin Signaling Pathway; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor Binding Protein 1; Interleukin-12; Interleukins; Life; Link; Lipids; Liver; Longevity; Luciferases; MAPK8 gene; Mammals; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Molecular; Monitor; Muscle; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Organism; Pathway interactions; Phosphoenolpyruvate Carboxylase; Phosphorylation; Phosphotransferases; Play; Production; Protein Binding; Proteins; Rattus; Regulation; Reporting; Role; Serum; Signal Pathway; Signal Transduction; Sphingomyelinase; Testing; Tissues; Ubiquitination; Up-Regulation; Work; aged; blood glucose regulation; cytokine; drug metabolism; frailty; glucose tolerance; improved; in vivo; insulin sensitivity; insulin signaling; interest; juvenile animal; liver function; novel; overexpression; promoter; receptor; research study; response; sarcopenia; small hairpin RNA; success; tissue repair; transcription factor; wasting

DESCRIPTION (provided by applicant): Our lab has a long standing interest in the mechanisms leading to the state of chronic, low-grade inflammation, which is an intrinsic component of the aging process and many aging-associated diseases. In the past we reported that the hepatic response to Interleukin 12 (IL-12), a major mediator of systemic inflammation, is augmented during aging leading to excessive production of IGFBP1, a protein that is secreted by the liver, binds to the Insulin-like Growth Factor 1 (IGF1), and neutralizes its bioactivity. Hepatic IL-12 hyperresponsiveness is caused by the intrinsic activation of an evolutionary conserved cellular stress response pathway involving neutral sphingomyelinase and its product, ceramide. Here we hypothesize that this IL-12 hyperresponsiveness impairs the insulin signaling pathway in liver. First, we will investigate how aging-associated IL-12 hyperresponsiveness affects the insulin pathway and will study the interactions between key molecules in the two cascades PI3K, Akt-1, and Foxo1 (for insulin), and ceramide, IRAK-1 and JNK (for IL-12). Studies will be done in isolated hepatocytes in vitro and in animals in vivo. Young, aged and aged calorie restricted rats will be used. The regulation of IGFBP1 mRNA transcription by the two pathways will be investigated. These molecular studies will be complemented by assays of insulin- and IGFBP1-dependent functions in vivo, which include tests of IGF1 bioactivity, muscle functions and glucose regulation. Throughout the experiments cause and effect relations will be tested by overexpression and silencing approach using adenovirus-mediated gene transfer. These studies may help to elucidate the cellular and molecular pathways responsible for muscle waste, frailty, and glucose dysregulation in the elderly. They may also reveal a novel mechanism for integration of inflammatory and metabolic signaling pathways and how aging affects these interactions. )

描述（由申请人提供）：我们的实验室长期以来一直对导致慢性低度炎症状态的机制感兴趣，慢性低度炎症是衰老过程和许多衰老相关疾病的内在组成部分。在过去，我们报道了肝脏对白细胞介素12（IL-12）（全身炎症的主要介质）的反应在衰老过程中增强，导致IGFBP 1的过量产生，IGFBP 1是一种由肝脏分泌的蛋白质，与胰岛素样生长因子1（IGF 1）结合，并中和其生物活性。肝脏IL-12高反应性是由涉及中性鞘磷脂酶及其产物神经酰胺的进化保守的细胞应激反应途径的内在激活引起的。 在这里，我们假设这种IL-12高反应性损害了肝脏中的胰岛素信号通路。首先，我们将研究衰老相关的IL-12高反应性如何影响胰岛素通路，并研究两个级联中关键分子PI 3 K，Akt-1和Foxo 1（胰岛素）和神经酰胺，IRAK-1和JNK（IL-12）之间的相互作用。将在体外分离的肝细胞和体内动物中进行研究。将使用年轻、年老和年老的热量限制大鼠。将研究这两种途径对IGFBP 1 mRNA转录的调节。这些分子研究将通过体内胰岛素和IGFBP 1依赖性功能的测定来补充，其中包括IGF 1生物活性、肌肉功能和葡萄糖调节的测试。在整个实验中，因果关系将通过使用腺病毒介导的基因转移的过表达和沉默方法来测试。这些研究可能有助于阐明老年人肌肉萎缩、虚弱和血糖失调的细胞和分子途径。它们还可能揭示炎症和代谢信号通路整合的新机制以及衰老如何影响这些相互作用。)