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，这些疾病极大地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。由于这些疾病在西方人群中的发病率明显增加，因此了解这些风险因素如何导致糖尿病和心脏病等代价高昂且使人衰弱的疾病的发病变得越来越重要。血管紧张素II （Ang II）是一种多肽激素，其分泌过多是高血压最常见的原因之一。虽然Ang II对血压的影响主要是通过其在血管床上的作用介导的，但这种激素也在多种其他组织中起作用。正是在这些组织中，如肝脏，Ang II激活了NF-:B转录因子，这一事件对胰岛素抵抗的发展至关重要。大量研究表明，NF-:B的激活是抑制胰岛素信号转导的机制之一。我们最近描述了一种新的细胞内信号通路，该通路介导肝细胞中Ang II依赖性NF-:B的激活，并涉及三个主要蛋白CARMA3， Bcl10和MALT1的协同作用。因此，我们假设这一信号通路可能对Ang ii依赖性胰岛素抵抗的发展至关重要。有趣的是，肥胖个体血浆中游离脂肪酸（FFAs）升高，也会激活肝脏NF-:B，从而促进胰岛素抵抗。由于Ang II和FFAs的作用具有许多共同的特征，我们进一步假设FFAs利用相同的CARMA3/Bcl10/MALT1途径激活NF-:B并诱导胰岛素抵抗状态。本研究的目标是进一步测试CARMA3、Bcl10和MALT1在阻断肝脏胰岛素信号传导中的作用，以及在慢性肥胖或II型胰岛素分泌过多的情况下促进胰岛素抵抗的生理状态。我们将通过以下四个具体目标来实现这一目标：(1)专门测试FFA诱导NF-:B是否实际上依赖于CARMA3/Bcl10/MALT1途径，(2)测试CARMA3/Bcl10/MALT1途径在介导肝脏胰岛素信号通路中的作用，(3)在小鼠模型中测试CARMA3、Bcl10和MALT1蛋白在介导Ang II和肥胖依赖性胰岛素抵抗中的作用。(4)测试基因删除CARMA3是否会在一种由于瘦素信号缺陷而容易产生胰岛素抵抗的小鼠品系中恢复正常的胰岛素敏感表型。公共卫生相关性：高血压或肥胖依赖型胰岛素抵抗的发生是发展为2型糖尿病的重要第一步，2型糖尿病通常是不可逆转的。因此，我们进一步探索胰岛素抵抗的分子机制是至关重要的，目的是开发新的策略来阻止糖尿病的进展。这一建议将探索一种新的信号通路，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。