A Novel Signaling Pathway Mediating Hypertension- and Obesity-dependent Insulin R

介导高血压和肥胖依赖性胰岛素 R 的新型信号通路

• 批准号: 7649758
• 负责人: PETER C LUCAS
• 金额: $ 35.14万
• 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/7649758
• 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; 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; public health relevance; 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个经常在一个人共存的条件星座，共同增强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症。由于西方人口中这些状况的发生率显着增加，因此了解这些危险因素如何促进糖尿病和心脏病的昂贵和使人衰弱的疾病的发作变得越来越重要。血管紧张素II（ANG II）是一种肽激素，其过量生产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来介导的，但激素也起作用。正是在这些组织中，例如肝脏，ANG II激活了NF-：B转录因子，这是胰岛素抵抗发展至关重要的事件。大量研究表明，NF-：B的激活是抑制性交叉对胰岛素信号转导的机制。我们最近描述了一种新型的细胞内信号通路，该途径介导了肝细胞中NF-：B的依赖性激活，并涉及三种主要蛋白Carma3，Bcl10和Malt1的共同努力。因此，我们假设该信号通路对于ANG II依赖性胰岛素抵抗的发展可能至关重要。有趣的是，在肥胖个体的血浆中升高的游离脂肪酸（FFA）也激活了肝NF-：B，从而有助于胰岛素抵抗。由于ANG II和FFA的作用具有许多特征，因此我们进一步假设FFA使用相同的CARMA3/BCL10/MALT1途径激活NF-：B：b并诱导胰岛素抵抗状态。该赠款提案的目的是进一步测试CARMA3，BCL10和MALT1在阻断肝脏中胰岛素信号传导以及在慢性肥胖或ANG II过量产生中促进胰岛素抵抗的生理状态方面的作用。我们将通过四个具体目标来实现这一目标，（1）特定测试NF-：B的诱导实际上是否取决于CARMA3/BCL10/MALT1途径，（2）测试Carma3/Bcl10/Malt1途径在用肝素胰岛素信号path和1 Carma的角色（3）测试Carma3/bcl10/Malt1途径在介导交叉序列中的作用（3）小鼠模型中的II-和肥胖依赖性胰岛素抵抗，（4）测试如果遗传删除CARMA3将在小鼠菌株中恢复正常的胰岛素敏感表型，该表型由于瘦素信号的缺陷而容易产生胰岛素耐药性。公共卫生相关性：高血压或肥胖依赖性胰岛素抵抗的发作是朝着2型糖尿病发展的第一步，这种疾病通常是不可逆的。因此，至关重要的是，我们要进一步探索胰岛素抵抗构成的分子机制，目的是制定阻止糖尿病进展的新型策略。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，因此可能为治疗干预提供了新的分子靶标。