Role of CD148 Tyrosine Phosphatase in Diabetic Nephropathy

CD148酪氨酸磷酸酶在糖尿病肾病中的作用

• 批准号: 9143095
• 负责人: TAKAMUNE TAKAHASHI
• 金额: $ 34.37万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143095
• 关键词: Agonist; Albuminuria; Angiogenesis Inhibitors; Angiogenic Factor; Angiogenic Proteins; Animals; Antibodies; Binding; Binding Proteins; Blood Vessels; Cell Culture Techniques; Country; Data; Defect; Development; Diabetic Nephropathy; Diabetic mouse; Disease; Elements; End stage renal failure; Endothelial Cells; Endothelial Growth Factors; Endothelium; Enzymes; Equilibrium; Gene Targeting; Glucose; Goals; Growth; Homeostasis; Hyperglycemia; KDR gene; Kidney; Knockout Mice; Ligands; Metabolic; Microvascular Dysfunction; Molecular; Mus; Mutant Strains Mice; PTPRJ gene; Pathway interactions; Play; Protein Tyrosine Phosphatase; Receptor Protein-Tyrosine Kinases; Role; Signal Pathway; Signal Transduction; Specificity; Therapeutic; Thrombospondin 1; Toxic effect; Transgenic Mice; Vascular Endothelial Growth Factors; angiogenesis; antiangiogenesis therapy; base; bevacizumab; cell growth; cell type; diabetic; driving force; extracellular; glomerular endothelium; hemodynamics; improved; in vivo; inhibitor/antagonist; knock-down; receptor; research study; response; small hairpin RNA; tool; treatment strategy

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the leading course of end-stage renal disease. Although multiple cell types are involved, DN is in essence a microvascular disease that develops as a result of a confluence of hemodynamic and metabolic perturbations. Endothelial cells and its disorders play a major role in this disease. In the past decade, a large body of studies has shown that excessive angiogenic signals and unregulated glomerular endothelial growth is a key pathogenic mechanism of DN. VEGF/VEGFR was shown to serve as a driving force of this. However, the role of anti-angiogenic pathway in this disease is largely unknown, yet the magnitude and spectrum of angiogenic signals are determined by the balance between angiogenic and anti- angiogenic signals. Given the fact that endothelial receptor protein tyrosine kinases (RPTKs) play a major role in transduction of angiogenic signals, we have advanced the hypothesis that endothelial receptor protein tyrosine phosphatases (RPTPs), counter-enzymes of RPTKs, may induce anti-angiogenic signals. We have isolated a receptor-type PTP CD148 from glomerular endothelial cells and shown that CD148 has a potent activity in suppressing endothelial growth factor signals (including VEGFR) and in inhibiting endothelial cell growth and angiogenesis. Further, we have recently found that thrombospondin-1(TSP1), an anti-angiogenic protein, acts as a ligand for CD148. These findings suggest that CD148 functions as a key regulator of glomerular angiogenic response. In this application we therefore define the role of CD148 in DN. Based on our preliminary data and anti-angiogenic activity of CD148, the following hypotheses were advanced; 1) CD148 expression/activity is decreased in diabetic glomerular endothelium. This enhances angiogenic endothelial growth factor signals (including VEGFR) and promotes the development and progression of DN. 2) Activation of CD148 suppresses angiogenic growth factor signals in diabetic glomerular endothelium and restores the functional and structural changes of DN. In aim 1, we will determine the role of CD148 in DN by manipulating CD148 expression in diabetic mice using conditional knockout and transgenic mice. In aim2, we will determine the effects of CD148 activation in DN by treating diabetic mice with the CD148 agonists, a specific TSP1 fragment and an agonistic antibody. Aim 3 will determine the endothelial signaling and function which is regulated by CD148 in diabetic glomerular endothelial cells, by knocking-down or activating CD148 in high-glucose glomerular endothelial culture and in diabetic glomeruli in vivo (in mice). Thus, the proposed studies will define the role of CD148 anti- angiogenic pathway in DN and explore a new strategy for the treatment of this disease.

描述（由申请人提供）：糖尿病性肾病（DN）是终末期肾脏疾病的主要过程。尽管涉及多种细胞类型，但DN本质上是一种微血管疾病，由于血液动力学和代谢扰动的汇合而发展。内皮细胞及其疾病在该疾病中起主要作用。 在过去的十年中，大量研究表明，过度的血管生成信号和不管制的肾小球内皮生长是DN的关键致病机制。 VEGF/VEGFR被证明是这种动力的动力。然而，抗血管生成途径在该疾病中的作用在很大程度上是未知的，但是血管生成信号的大小和光谱取决于血管生成和抗血管生成信号之间的平衡。鉴于内皮受体蛋白酪氨酸激酶（RPTK）在血管生成信号转导中起主要作用，因此我们提出了一个假设，即内皮受体蛋白酪氨酸磷酸酶（RPTPS）（RPTPS），RPTK的反酶，可能诱导抗抗血管生成信号。我们已经从肾小球内皮细胞中分离了受体型PTP CD148，并表明CD148在抑制内皮生长因子信号（包括VEGFR）以及抑制内皮细胞生长和血管生成方面具有有效的活性。此外，我们最近发现，抗血管生成蛋白的血小板传播1（TSP1）充当CD148的配体。这些发现表明，CD148是肾小球血管生成反应的关键调节剂。因此，在此应用中，我们定义了CD148在DN中的作用。基于我们的初步数据和CD148的抗血管生成活性，以下假设得到了进展。 1）CD148在糖尿病肾小球内皮中降低表达/活性。这增强了血管生成的内皮生长因子信号（包括VEGFR），并促进DN的发展和进展。 2）CD148的激活抑制糖尿病肾小球内皮中的血管生成因子信号，并恢复DN的功能和结构变化。 在AIM 1中，我们将使用条件敲除和转基因小鼠在糖尿病小鼠中操纵CD148的表达来确定CD148在DN中的作用。在AIM2中，我们将通过使用CD148激动剂，特定的TSP1片段和激动剂抗体来确定DN中CD148激活的影响。 AIM 3将通过在高葡萄糖肾小球肾小球内皮培养中敲击或激活CD148在糖尿病性肾小球内皮细胞中受CD148调节的内皮信号传导和功能。因此，拟议的研究将定义CD148抗血管生成途径在DN中的作用，并探索一种治疗该疾病的新策略。

项目成果

The effects of CD148 Q276P/R326Q polymorphisms in A431D epidermoid cancer cell proliferation and epidermal growth factor receptor signaling.

• DOI: 10.1002/cnr2.1566
• 发表时间: 2022-09
• 期刊: CANCER REPORTS
• 影响因子: 1.7
• 作者: He, Lilly;Takahashi, Keiko;Pasic, Lejla;Narui, Chikage;Ellinger, Philipp;Grundmann, Manuel;Takahashi, Takamune
• 通讯作者: Takahashi, Takamune