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: 8611325
• 负责人: PETER C LUCAS
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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/8611325
• 关键词: Novel; signal; pathway; mediating; Hypertension

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通常在个体中共存的疾病，这些疾病共同极大地增加了发展为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显著增加，了解这些风险因素如何导致代价高昂且使人虚弱的糖尿病和心脏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，其过度分泌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它在血管床上的作用来调节的，但这种激素也在其他各种组织中发挥作用。正是在这些组织中，如肝脏，Ang II激活了核因子-：B转录因子，这一事件是胰岛素抵抗发展的核心。大量研究表明，核因子-B的激活是抑制胰岛素信号转导串扰的一种机制。我们最近描述了一种新的细胞内信号通路，它介导了肝细胞中Ang II依赖的NF：B的激活，涉及三个主要蛋白质CARMA3、Bcl10和MALT1的协同作用。因此，我们推测这一信号通路可能在血管紧张素Ⅱ依赖型胰岛素抵抗的发生发展中起关键作用。有趣的是，肥胖者血浆中升高的游离脂肪酸(FFAs)也会激活肝脏的核因子-B，从而导致胰岛素抵抗。由于Ang II和FFAs的作用有许多共同的特征，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。这项拨款提案的目的是进一步测试CARMA3、Bcl10和MALT1在阻断肝脏中的胰岛素信号，以及在慢性肥胖或Ang II生产过剩的背景下促进胰岛素抵抗的生理状态中的作用。我们将通过四个具体目标来实现这一目标，这四个目标是：(1)具体测试FFA对NF-：B的诱导是否确实依赖于CARMA3/Bcl10/MALT1通路；(2)测试CARMA3/Bcl10/MALT1通路在介导与肝脏胰岛素信号通路的串扰中的作用；(3)在小鼠模型中测试CARMA3、Bcl10和MALT1蛋白在介导Ang II和肥胖依赖的胰岛素抵抗中的作用；以及(4)测试通过基因删除CARMA3是否可以恢复由于瘦素信号缺陷而容易发生胰岛素抵抗的小鼠的正常胰岛素敏感表型。公共卫生相关性：高血压或肥胖依赖型胰岛素抵抗的出现是发展成2型糖尿病的第一个重要步骤，而2型糖尿病通常是不可逆转的。因此，我们必须进一步探索胰岛素抵抗的分子机制，目标是开发阻止糖尿病进展的新策略。这项提议将探索一种新的信号通路，该通路可能是导致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。