Novel signal pathway mediating Hypertension/Obesity-dependent Insulin Resistance

介导高血压/肥胖依赖性胰岛素抵抗的新信号通路

• 批准号: 8081071
• 负责人: PETER C LUCAS
• 金额: $ 31.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081071
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adaptor Signaling Protein; Angiotensin II; Angiotensins; Animals; Applications Grants; Blood Pressure; Chronic; Complex; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Disease; Event; Fatty acid glycerol esters; Genetic; Goals; Health; Heart Diseases; Hepatic; Hepatocyte; Hormones; Hypertension; In Vitro; Incidence; Individual; Infusion procedures; Insulin; Insulin Resistance; Insulin Signaling Pathway; Knock-out; Learning; Leptin; Link; Lipids; Liver; Mediating; Metabolic syndrome; Modeling; Molecular; Molecular Target; Mouse Strains; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pathogenesis; Pathway interactions; Peptides; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Plasma; Play; Population; Protein Kinase C; Proteins; Risk; Risk Factors; Role; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; adipokines; design; feeding; in vivo; insight; insulin sensitivity; insulin signaling; mouse model; novel; novel strategies; peptide hormone; prevent; resistin; response; transcription factor; vascular bed

DESCRIPTION (provided by applicant): The Metabolic Syndrome defines a constellation of conditions, often co-existing in an individual, that together greatly enhance the risk of developing diabetes and coronary artery disease. Two of the major components of the Metabolic Syndrome are hypertension and obesity. Since there has been a marked increase in the incidence of these conditions within the western population, it is becoming increasingly important to understand how these risk factors contribute to the onset of the costly and debilitating diseases of diabetes and heart disease. Angiotensin II (Ang II) is a peptide hormone whose overproduction is one of the most common causes of hypertension. While the effects of Ang II on blood pressure are primarily mediated through its actions on the vascular bed, the hormone also acts in a variety of other tissues. It is in these tissues, such as liver, that Ang II activates the NF-:B transcription factor, an event that is central to the development of insulin resistance. Numerous studies have shown that activation of NF-:B serves as a mechanism for inhibitory cross-talk with insulin signal transduction. We recently described a novel intracellular signaling pathway that mediates Ang II- dependent activation of NF-:B in hepatocytes, and involves the concerted efforts of three principal proteins, CARMA3, Bcl10, and MALT1. Thus, we hypothesize that this signaling pathway may be critical to the development of Ang II-dependent insulin resistance. Interestingly, free fatty acids (FFAs), which are elevated in the plasma of obese individuals, also activate hepatic NF-:B and thereby contribute to insulin resistance. Since the actions of Ang II and FFAs share a number of features, we further hypothesize that FFAs utilize the same CARMA3/Bcl10/MALT1 pathway to activate NF-:B and induce a state of insulin resistance. The goal of this grant proposal is to further test the role of CARMA3, Bcl10, and MALT1 in blocking insulin signaling in liver, and in promoting the physiologic state of insulin resistance in the setting of chronic obesity or Ang II overproduction. We will accomplish this goal through four specific aims that (1) specifically test whether FFA induction of NF-:B does in fact depend on the CARMA3/Bcl10/MALT1 pathway, (2) test the role of the CARMA3/Bcl10/MALT1 pathway in mediating cross-talk with hepatic insulin signaling pathways, (3) test the role of the CARMA3, Bcl10, and MALT1 proteins in mediating Ang II- and obesity-dependent insulin resistance in a mouse model, and (4) test if genetically deleting CARMA3 will restore a normal insulin-sensitive phenotype in a strain of mice that are prone to developing insulin resistance because of defective Leptin signaling. PUBLIC HEALTH RELEVANCE: The onset of hypertension- or obesity-dependent insulin resistance is a first major step toward the development of type 2 diabetes, a condition that is typically irreversible. It is therefore critical that we further explore the molecular mechanisms that underlie insulin resistance, with the goal of developing novel strategies for blocking the progression to diabetes. This proposal will explore a novel signaling pathway that may underlie some of the most common causes of insulin resistance and may thereby provide new molecular targets for therapeutic intervention.

描述（由申请人提供）：代谢综合征定义了一系列疾病，通常在个体中共存，这些疾病共同大大增加了患糖尿病和冠状动脉疾病的风险。代谢综合征的两个主要组成部分是高血压和肥胖。由于西方人群中这些疾病的发病率显著增加，因此了解这些风险因素如何导致糖尿病和心脏病等昂贵且使人衰弱的疾病的发病变得越来越重要。血管紧张素II（AngII）是一种肽类激素，其过量产生是高血压最常见的原因之一。虽然血管紧张素II对血压的影响主要是通过其对血管床的作用介导的，但该激素也在各种其他组织中起作用。正是在这些组织中，如肝脏，Ang II激活NF-：B转录因子，这是胰岛素抵抗发展的中心事件。大量研究表明，NF-：B的激活是抑制胰岛素信号转导的一种机制。我们最近描述了一种新的细胞内信号通路，其介导肝细胞中NF-：B的Ang II依赖性活化，并且涉及三种主要蛋白质CARMA 3、Bcl 10和MALT 1的协同作用。因此，我们推测，这一信号通路可能是关键的发展血管紧张素II依赖性胰岛素抵抗。有趣的是，肥胖个体血浆中升高的游离脂肪酸（FFA）也激活肝脏NF-：B，从而导致胰岛素抵抗。由于血管紧张素II和游离脂肪酸的作用具有许多共同的特征，我们进一步假设游离脂肪酸利用相同的CARMA 3/Bcl 10/MALT 1途径激活NF-：B并诱导胰岛素抵抗状态。这项资助提案的目标是进一步测试CARMA 3，Bcl 10和MALT 1在阻断肝脏胰岛素信号传导中的作用，以及在慢性肥胖或Ang II过度产生的情况下促进胰岛素抵抗的生理状态。我们将通过四个具体目标来实现这一目标，即（1）具体测试FFA诱导NF-：B是否确实依赖于CARMA 3/Bcl 10/MALT 1通路，（2）测试CARMA 3/Bcl 10/MALT 1通路在介导与肝脏胰岛素信号通路的串扰中的作用，（3）测试CARMA 3、Bcl 10和MALT 1蛋白在小鼠模型中介导Ang II和肥胖依赖性胰岛素抵抗中的作用，以及（4）测试基因缺失CARMA 3是否会在由于瘦素信号缺陷而易于发生胰岛素抵抗的小鼠品系中恢复正常的胰岛素敏感表型。公共卫生关系：高血压或肥胖依赖性胰岛素抵抗的发生是2型糖尿病发展的第一个重要步骤，2型糖尿病是一种典型的不可逆疾病。因此，我们必须进一步探索胰岛素抵抗的分子机制，以开发新的策略来阻止糖尿病的进展。该提案将探索一种新的信号通路，该通路可能是胰岛素抵抗的一些最常见原因的基础，从而可能为治疗干预提供新的分子靶点。