TNF-ALPHA AND BMP2-WNT SIGNALING IN DIABETIC VASCULAR DISEASE

糖尿病血管疾病中的 TNF-α 和 BMP2-WNT 信号转导

• 批准号: 7762246
• 负责人: DWIGHT A. TOWLER
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762246
• 关键词: Amputation; Anti-Inflammatory Agents; Anti-inflammatory; Aorta; Arteries; BMP2 gene; Benign; Blood Vessels; Calcium; Caliber; Cells; Characteristics; Clinical; Complement; Controlled Study; Critiques; Dactinomycin; Data; Diabetes Mellitus; Diabetic Angiopathies; Diabetic macrovascular disease; Diet; Epidemic; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Glomerular Capillary; Goals; Hand; Health; Health Care Costs; Heart; Inflammation; Kidney Diseases; Kidney Glomerulus; Laboratories; Lead; Life Style; Longevity; Manuscripts; Medial; Mediating; Messenger RNA; Modeling; Molecular; Mus; Muscle; Myofibroblast; NADPH Oxidase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidases; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Phenotype; Physiology; Plethysmography; Recombinants; Recommendation; Regulation; Retina; Retinal; Risk; Role; Signal Transduction; Societies; Sodium Salicylate; Structure; Study models; Superoxides; TNF gene; TNFSF11 gene; Techniques; Testing; Tissues; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Diseases; Vascular calcification; WNT Signaling Pathway; acetovanillone; attenuation; calcification; cost; diabetic; digital; experience; feeding; foot; human TNF protein; improved; in vivo; infliximab; inhibitor/antagonist; insight; intraperitoneal; macrovascular disease; mortality; novel strategies; osteogenic; preference; pressure; prevent; promoter; research study; response; salicylate; vascular inflammation

DESCRIPTION (provided by applicant): Westernized societies are experiencing an epidemic of type II diabetes (T2DM), related to life-style, obesity, and longevity. T2DM is a systemic vascular disorder; wide-spread low grade arterial inflammation, elevated TNF-alpha levels, & oxidative stresses disrupt macrovascular (e.g., heart, aorta) & microvascular (e.g. retina, renal glomerulus) functions. A highly characteristic feature of T2DM is medial artery calcification (MAC). The negative consequences of reduced aortofemoral compliance of MAC have emerged; MAC perturbs normal Windkessel physiology, causing systolic & diastolic dysfunction that increases mortality & amputation risk. The ability to prevent or treat MAC represents an unmet clinical need. A better understanding of how diabetes and kidney disease (CKD) promote MAC will provide insights useful for devising new strategies to reduce vascular calcium load, preserve aortic compliance, & improve vascular function. Recent data have identified activated aortic BMP2-Msx2-Wnt signaling in diabetic MAC--all inhibited by infliximab. The chief goal of this project is to assess how targeting these signals can improve aortic calcification, structure, & compliance. Aim 1: "To test whether inhibition of arterial BMP2- Wnt induction with theTNF-alpha antagonist infliximab or salicylate improves aortic compliance in diabetic vascular disease." By assessing aortic pressure- diameter relationships using ex vivo video plethysmography, we will establish the relationships between TNF-alpha & aortic calcium accumulation, Wnt signaling, and stiffness in a relevant T2DM model--the TOPGAL+; LDLR-/- mouse fed diabetogenic high fat diets (HFD). Comparison will be made with responses to the RANKL inhibitor, OPG. Aim 2: "To characterize the mechanisms whereby TNF- alpha signaling via NADPH oxidase promotes Msx2 gene transcription in aortic adventitial myofibroblasts." The NAPDH oxidase inhibitor, apocynin, inhibits Msx2 induction by TNF-alpha (transcriptionally mediated). By identifying the signaling cascades conveying Msx2 induction in response to TNF-alpha, novel strategies can be devised to inhibit vascular calcification. Aim 3: "To identify if NADPH oxidase signaling is required for induction of aortic BMP2-Msx-2-Wnt cascades in T2DM, using p47phox- /-; TOPGAL+; LDLR-/- mice as a model." By phenotyping p47phox-/-; TOPGAL+; LDLR-/- and p47phox+/-;TOPGAL+; LDLR-/- controls, we assess whether this TNF- regulated redox pathway contributes to aortic BMP2-Msx2-Wnt activation by HFD.

描述（由申请人提供）：西方社会正在经历与生活方式，肥胖和寿命有关的II型糖尿病（T2DM）流行。 T2DM是一种全身性血管疾病。广泛的低级动脉炎症，TNF-α水平升高和氧化应激破坏大血管（例如心脏，主动脉）和微血管（例如视网膜，肾肾小球）功能。 T2DM的高度特征是内侧动脉钙化（MAC）。 MAC的Riontofemoral依从性降低的负面后果已经出现。 MAC渗透正常的Windkessel生理学，导致收缩和舒张功能障碍增加死亡率和截肢风险。预防或治疗MAC的能力代表了未满足的临床需求。更好地了解糖尿病和肾脏疾病（CKD）如何促进MAC将提供有关设计新策略以减少血管钙负荷，保持主动脉依从性并改善血管功能的见解。最近的数据已经确定了糖尿病MAC中激活的主动脉BMP2-MSX2-WNT信号传导，这一切都被英夫利昔单抗抑制。该项目的主要目标是评估针对这些信号如何改善主动脉钙化，结构和合规性。目标1：“测试抑制动脉BMP2-Wnt诱导对thetnf-alpha拮抗剂英夫利昔单抗或水杨酸酯的诱导是否可以改善糖尿病血管疾病的主动脉依从性。”通过使用离体视频散布图评估主动脉压力直径关系，我们将在相关T2DM模型中建立TNF-Alpha和主动脉钙积累，Wnt信号传导和刚度之间的关系 - Topgal+； LDLR - / - 喂养糖尿病性高脂饮食（HFD）。比较将与对RANKL抑制剂OPG的响应进行比较。目标2：“要表征通过NADPH氧化酶TNF-Alpha信号传导的机制，可以促进主动脉质体肌纤维细胞中的MSX2基因转录。” NAPDH氧化酶抑制剂Apocynin抑制TNF-Alpha（转录介导）的MSX2诱导。通过识别响应TNF-Alpha传达MSX2诱导的信号传导级联反应，可以设计出新的策略来抑制血管钙化。 AIM 3：“使用p47phox- / - ; topgal+; topgal+; ldlr - / - 小鼠作为模型，确定是否需要NADPH氧化酶信号传导来诱导T2DM中主动脉BMP2-MSX-WNT级联反应。”通过表型P47phox - / - ; topgal+; ldlr - / - 和p47phox +/-; topgal+; LDLR - / - 对照，我们评估该TNF调控的氧化还原途径是否有助于HFD主动脉BMP2-MSX2-WNT激活。