TRPC Channels in the Metabolic Syndrome

代谢综合征中的 TRPC 通道

• 批准号: 9066774
• 负责人: Alexander G. Obukhov
• 金额: $ 53.31万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066774
• 关键词: Adult; Aldosterone; American; Angiotensin II; Animal Model; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Biochemical; Biological; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cell Proliferation; Cell membrane; Central obesity; Cessation of life; Characteristics; Cholesterol; Complementary DNA; Coronary; Coronary Arteriosclerosis; Coronary artery; Development; Disease Progression; Dominant-Negative Mutation; Down-Regulation; Dyslipidemias; Electrophysiology (science); Electroporation; Exhibits; Experimental Designs; Family suidae; Fluorometry; Functional disorder; Gene Delivery; Glucose Intolerance; Goals; Histamine; Hormones; Human; Hypertension; Injury; Insulin Resistance; Ion Channel; Isometric Exercise; Lead; Measurement; Mediating; Metabolic syndrome; Microinjections; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Molecular; Myocardial Infarction; Obesity; Organ Culture Techniques; Outcome; Phosphotransferases; Plasma; Prevalence; Renin; Renin-Angiotensin-Aldosterone System; Research; Role; Sarcoplasmic Reticulum; Sclerosis; Severities; Signal Pathway; Signal Transduction; Site; Smooth Muscle Myocytes; Spironolactone; Stenosis; Surface; TRP channel; Techniques; Therapeutic Effect; Ultrasonography; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; Vasoconstrictor Agents; clinically significant; defined contribution; fasting glucose; fluorescence imaging; in vivo; inhibitor/antagonist; injured; migration; neointima formation; new therapeutic target; novel; novel strategies; oxidant stress; prevent; programs; receptor; receptor operated channel; response; small hairpin RNA; sound; targeted delivery; treatment strategy; voltage

DESCRIPTION (provided by applicant): Canonical TRP channels (TRPC) form store- and receptor-operated Ca2+-permeable channels in the plasma membrane of vascular smooth muscle cells. TRPCs have been implicated in regulating vascular tone and smooth muscle cell proliferation. This proposal will define the molecular roles of TRPC channels during coronary artery remodeling associated with metabolic syndrome (MetS). MetS is characterized by central obesity, elevated plasma cholesterol and fasting glucose, hypertension, insulin resistance, and atherosclerosis. The prevalence of MetS among adults in the USA is 24%. In this research program, we will utilize the MetS Ossabaw pig model that exhibits all of the characteristics of MetS, including the overactive renin-angiotensin- aldosterone system (RAAS). We demonstrated that the expression levels of TRPC1 and TRPC6 channels are markedly elevated in MetS Ossabaw pig coronary arteries exhibiting atherosclerosis and hypercontractility. Consistently, freshly isolated MetS coronary artery smooth muscle cells had elevated store-/receptor-operated Ca2+ influx and large store-/receptor-operated TRPC-like currents. Since angiotensin II and aldosterone are positive regulators of TRPC expression, we hypothesize that, in MetS, the overactive RAAS upregulates TRPC1 and TRPC6 expression, which drives increased coronary smooth muscle cell proliferation and coronary artery hypercontractility. The following Specific Aims will be pursued: 1) To determine how the molecular expression of TRPCs is altered during the MetS-associated remodeling of coronary artery smooth muscle cells; 2) To define the contribution of TRPCs to endogenous store- and receptor-activated Ca2+ influx/currents in control and MetS coronary artery smooth muscle cells; 3) To determine whether the functional expression of endogenous TRPC channels is directly regulated by RAAS components, angiotensin II and Aldo, in coronary artery smooth muscle cells; 4) To determine whether the in vivo, coronary artery targeted down- regulation of TRPCs slows atheroma progression and decreases coronary artery hypercontractility in MetS pigs. During this research program, we will use molecular biological, biochemical, electrophysiological, and fluorescence imaging approaches as well as intravascular ultrasound, isometric tension and coronary artery ring lumen area measurements. Additionally, a coronary artery targeted delivery approach will be employed to deploy shRNAs and cDNA constructs into the coronary artery wall in vivo. Importantly, we will determine the distinct roles of TRPC1 and TRPC6 during MetS-associated NATIVE atherosclerosis progression.

描述（由申请人提供）：典型TRP通道（TRPC）在血管平滑肌细胞的质膜中形成钙池和受体操纵的Ca2+通透通道。 TRPC 与调节血管张力和平滑肌细胞增殖有关。该提案将定义 TRPC 通道在与代谢综合征 (MetS) 相关的冠状动脉重塑过程中的分子作用。 MetS 的特征是中心性肥胖、血浆胆固醇和空腹血糖升高、高血压、胰岛素抵抗和动脉粥样硬化。美国成年人中 MetS 的患病率为 24%。在本研究项目中，我们将利用 MetS Ossabaw 猪模型，该模型表现出 MetS 的所有特征，包括过度活跃的肾素-血管紧张素-醛固酮系统 (RAAS)。我们证明，在表现出动脉粥样硬化和过度收缩的 MetS Ossabaw 猪冠状动脉中，TRPC1 和 TRPC6 通道的表达水平显着升高。一致地，新鲜分离的 MetS 冠状动脉平滑肌细胞具有升高的钙池/受体操作的 Ca2+ 流入和大量的钙池/受体操作的 TRPC 样电流。由于血管紧张素 II 和醛固酮是 TRPC 表达的正调节因子，我们推测，在 MetS 中，过度活跃的 RAAS 上调 TRPC1 和 TRPC6 表达，从而导致冠状动脉平滑肌细胞增殖增加和冠状动脉收缩过度。将追求以下具体目标： 1) 确定在与 MetS 相关的冠状动脉平滑肌细胞重塑过程中 TRPC 的分子表达如何改变； 2) 确定 TRPC 对对照和 MetS 冠状动脉平滑肌细胞中内源性储存和受体激活的 Ca2+ 流入/电流的贡献； 3) 确定冠状动脉平滑肌细胞内源性TRPC通道的功能表达是否受RAAS成分血管紧张素II和Aldo直接调节； 4) 确定体内 TRPC 的冠状动脉靶向下调是否会减缓 MetS 猪中的动脉粥样硬化进展并降低冠状动脉过度收缩性。在这个研究项目中，我们将使用分子生物学、生化、电生理学和荧光成像方法以及血管内超声、等长张力和冠状动脉环管腔面积测量。此外，将采用冠状动脉靶向递送方法将 shRNA 和 cDNA 构建体部署到体内冠状动脉壁中。重要的是，我们将确定 TRPC1 和 TRPC6 在 MetS 相关的天然动脉粥样硬化进展过程中的不同作用。

项目成果

Phenylephrine, a common cold remedy active ingredient, suppresses uterine contractions through cAMP signalling.

去氧肾上腺素是一种普通感冒药活性成分，通过 cAMP 信号传导抑制子宫收缩。

• 发表时间: 2018
• 影响因子: 4.6
• 作者: Chen, Xingjuan;Meroueh, Marya;Mazur, Gabriela;Rouse, Evan;Hundal, Karmjot Singh;Stamatkin, Christopher W;Obukhov, Alexander G
• 通讯作者: Obukhov, Alexander G

PKC-dependent Phosphorylation of the H1 Histamine Receptor Modulates TRPC6 Activity.

H1 组胺受体的 PKC 依赖性磷酸化调节 TRPC6 活性。

• 发表时间: 2014
• 影响因子: 6
• 作者: Chen, Xingjuan;Egly, Christian;Riley, Ashley M;Li, Wennan;Tewson, Paul;Hughes, Thomas E;Quinn, Anne Marie;Obukhov, Alexander G
• 通讯作者: Obukhov, Alexander G

Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice.

内皮细胞特异性删除 P2Y2 受体可促进动脉粥样硬化易感 ApoE 缺失小鼠的斑块稳定性。

• 发表时间: 2017-01
• 作者: Chen, Xingjuan;Qian, Shaomin;Hoggatt, April;Tang, Hongying;Hacker, Timothy A;Obukhov, Alexander G;Herring, Paul B;Seye, Cheikh I
• 通讯作者: Seye, Cheikh I

Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking.

小分子 CaVα1–CaVβ 拮抗剂可抑制神经元电压门控钙通道运输。

• 发表时间: 2018
• 影响因子: 11.1
• 作者: Chen, Xingjuan;Liu, Degang;Zhou, Donghui;Si, Yubing;Xu, David;Stamatkin, Christopher W;Ghozayel, Mona K;Ripsch, Matthew S;Obukhov, Alexander G;White, Fletcher A;Meroueh, Samy O
• 通讯作者: Meroueh, Samy O

The TRPC6 inhibitor, larixyl acetate, is effective in protecting against traumatic brain injury-induced systemic endothelial dysfunction.

TRPC6 抑制剂乙酸落叶松酯可有效预防创伤性脑损伤引起的全身内皮功能障碍。

• 发表时间: 2019-01-31
• 作者: Chen, Xingjuan;Taylor;Riley, Ashley M;Herring, B Paul;White, Fletcher A;Obukhov, Alexander G
• 通讯作者: Obukhov, Alexander G