Protein Tyrosine Phosphatase-1B and vascular signal transduction in obesity

肥胖中的蛋白酪氨酸磷酸酶-1B 与血管信号转导

• 批准号: 407333233
• 负责人: Professorin Dr. Katrin Schäfer
• 金额: --
• 依托单位: Kardiologie I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407333233?language=en
• 关键词: Protein; Tyrosine; Phosphatase; 1B; vascular

Overexpression of counterregulatory mediators, such as protein tyrosine phosphatase 1B (PTP1B), has been implicated in disorders of central nervous control mechanisms of food intake and energy balance and the development of leptin and insulin resistance in obesity. Substrates of PTP1B include receptor tyrosine kinases, but also structural proteins such as caveolin-1, proteases such as calpain, or integrin modulators such as Src kinase and cortactin, i.e. factors with critical relevance for vascular homeostasis. However, the importance of PTP1B for the signal transduction of vascular cells and the vascular complications of obesity are incompletely understood. Our own preliminary work shows that the lack of PTP1B in endothelial cells increases the expression of caveolin-1 and the formation of reactive oxygen species and accelerates the development of senescence, while mice with genetic deletion of PTP1B in smooth muscle cells develop an increased perivascular fibrosis after vascular wall injury. Moreover, PTP1B has been shown to interfere with the tropomyosin receptor kinase (Trk)-mediated signal transduction of neurotrophins. Neurotrophins and their receptors are expressed in adipose tissue and vascular cells, among others, and first data suggest functions in the control of vascular tone, smooth muscle cell proliferation and extracellular matrix production. In the proposed project, the importance of PTP1B for disorders of vascular function will be examined and the underlying mechanisms elucidated using primary cells, animal models and patient biomaterial. On the basis of (own) preparatory work, the significance of PTP1B for the development of aging processes in the vascular endothelium will be clarified and the involved mediators will be identified. In addition, it will be investigated whether and how oxidative stress and senescence contribute to perivascular fibrosis in the absence of PTP1B in myofibroblasts and perivascular progenitor cells. In addition, we will determine how absence of the neurotrophin receptor TrkB in smooth muscle cells affects neointima formation and how obesity or PTP1B influence the expression of neurotrophic mediators and their receptors in the vessel wall and perivascular adipose tissue.

反调节介质，如蛋白酪氨酸磷酸酶1B（PTP 1B）的过表达，已被牵连在食物摄入和能量平衡的中枢神经控制机制的障碍和肥胖症的瘦素和胰岛素抵抗的发展。PTP 1B的底物包括受体酪氨酸激酶，但也包括结构蛋白如小窝蛋白-1、蛋白酶如钙蛋白酶、或整联蛋白调节剂如Src激酶和皮质蛋白，即与血管稳态具有关键相关性的因子。然而，PTP 1B对血管细胞信号转导和肥胖的血管并发症的重要性还不完全清楚。我们自己的初步工作表明，内皮细胞中PTP 1B的缺乏增加了小窝蛋白-1的表达和活性氧的形成，加速了衰老的发展，而平滑肌细胞中PTP 1B基因缺失的小鼠在血管壁损伤后血管周围纤维化增加。此外，PTP 1B已被证明干扰原肌球蛋白受体激酶（Trk）介导的神经营养因子的信号转导。神经营养因子及其受体在脂肪组织和血管细胞等中表达，并且第一数据表明在控制血管张力、平滑肌细胞增殖和细胞外基质产生中的功能。在拟议的项目中，PTP 1B对血管功能障碍的重要性将被检查，并使用原代细胞，动物模型和患者生物材料阐明其潜在机制。在（自己的）准备工作的基础上，PTP 1B对血管内皮衰老过程的发展的意义将得到澄清，并将确定所涉及的介质。此外，将研究在肌成纤维细胞和血管周围祖细胞中不存在PTP 1B的情况下，氧化应激和衰老是否以及如何促成血管周围纤维化。此外，我们将确定如何在平滑肌细胞中缺乏神经营养因子受体TrkB影响新生内膜的形成，以及肥胖或PTP 1B如何影响血管壁和血管周围脂肪组织中神经营养介质及其受体的表达。