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

蛋白质酪氨酸磷酸酶1B （PTP1B）等反调节介质的过度表达与中枢神经控制食物摄入和能量平衡机制的紊乱以及肥胖中瘦素和胰岛素抵抗的发展有关。PTP1B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，或整合素调节剂，如Src激酶和内联素，即与血管稳态相关的关键因素。然而，PTP1B在血管细胞信号转导和肥胖血管并发症中的重要性尚不完全清楚。我们自己的前期工作表明，内皮细胞中PTP1B的缺乏增加了caveolin-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PTP1B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，PTP1B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，初步数据表明其功能包括控制血管张力、平滑肌细胞增殖和细胞外基质的产生。在本项目中，我们将通过原代细胞、动物模型和患者生物材料来研究PTP1B在血管功能障碍中的重要性，并阐明其潜在机制。在前期准备工作的基础上，阐明PTP1B在血管内皮衰老过程发展中的重要意义，并确定其所涉及的介质。此外，我们还将研究在肌成纤维细胞和血管周围祖细胞缺乏PTP1B的情况下，氧化应激和衰老是否以及如何促进血管周围纤维化。此外，我们将确定平滑肌细胞中神经营养因子受体TrkB的缺失如何影响新内膜的形成，以及肥胖或PTP1B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。

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.