Adenosine signaling protects the glomerular endothelium

腺苷信号传导保护肾小球内皮

基本信息

批准号：
7875001
负责人：
David J Friedman
金额：
$ 8.7万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7875001
关键词：
Adenosine Adenosine A1 Receptor Adverse effects Affect Agonist Albuminuria Angiogenesis Inhibitors Antibodies Antineoplastic Agents Binding Cancer Patient Cell surface Chemotherapy-Oncologic Procedure Clinical Clinical Trials Complication Data Defect Disease Dose-Limiting Endothelial Cells Endothelium Enzymes Fetus Functional disorder Future Goals Growth Factor Health Hydrolysis Hypertension Inflammation Inflammatory Injury Kidney Knockout Mice Lead Link Malignant Neoplasms Maps Mediating Molecular Mus Nitric Oxide Nucleotides Pathway interactions Patients Pharmacotherapy Placenta Pre-Eclampsia Predisposition Pregnancy Pregnancy Complications Prevention Production Proteinuria Purinergic P1 Receptors Regimen Renal carcinoma Resistance Signal Transduction Supportive care Testing Thrombosis Time Toxic effect Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular Endothelium Wild Type Mouse Work adenosine receptor activation angiogenesis antiangiogenesis therapy base bench to bedside cancer therapy cancer type clinical application extracellular fetal glomerular endothelium inhibitor/antagonist injured mouse model overexpression podocyte prevent protective effect public health relevance receptor response tumor

项目摘要

DESCRIPTION (provided by applicant): Preeclampsia and angiogenesis inhibitors used to treat cancer are two common causes of severe glomerular endothelial injury. The glomerular endothelium depends on vascular endothelial growth factor (VEGF) made by podocytes to maintain endothelial stability and integrity. A deficiency of VEGF signaling at the glomerular endothelium causes endotheliosis, a dysfunction of endothelial cells manifested clinically by proteinuria and hypertension. This disorder is seen in both preeclampsia (due to a soluble receptor that blocks VEGF signaling) and as a complication of cancer treatment with several angiogenesis inhibitors directed against VEGF. The clinical consequences in preeclampsia include increased maternal and fetal complications, while with angiogenesis-based cancer treatment the consequence is dose-limiting toxicity for highly effective anti-cancer drugs. Extracellular nucleotides such as ATP, as well as their hydrolysis product adenosine, are important factors in determining the health of the endothelium. In general, extracellular ATP is pro-inflammatory and pro-thrombotic, while adenosine protects against inflammation and thrombosis. Cell surface enzymes called ectonucleotidases convert extracellular ATP to adenosine, promoting a stable milieu for the vascular endothelium. We hypothesize that adenosine signaling via cell surface adenosine receptors is an important component of protection from injury in settings of VEGF deficiency. In aim 1 of this proposal, we will determine if a non-selective adenosine agonist can reverse albuminuria and renal injury in mice with VEGF deficiency. In aim 2, we will identify the specific adenosine receptor (A1, A2a, A2b, or A3) that mediates the protective effect of adenosine on the glomerular endothelium by using selective adenosine agonists and antagonists to ameliorate or accentuate renal injury in our mouse model. These studies will help define pathways that mediate renal injury in states of VEGF deficiency, and will also identify specific targets for drug therapy. A wide range of adenosine agonists and antagonists have already been developed, with several in clinical trials, so that clinical applications could be considered without a long delay between bench and bedside. PUBLIC HEALTH RELEVANCE: In diseases such as pre-eclampsia or complications of some cancer therapies, the kidney is injured by lack of important growth factors. We are developing strategies that might allow prevention or reversal of this kidney injury. Our findings may reduce severe complications of pregnancy or allow for more effective delivery of cancer chemotherapy.

描述（由申请人提供）：用于治疗癌症的先兆子痫和血管生成抑制剂是严重肾小球内皮损伤的两个常见原因。肾小球内皮取决于足细胞生长的血管内皮生长因子（VEGF），以维持内皮稳定性和完整性。 VEGF信号在肾小球内皮中的缺乏会导致内皮病，内皮病是临床上由蛋白尿和高血压表现出的内皮细胞功能障碍。在子痫前期（由于阻断VEGF信号传导的可溶受体）和针对VEGF的几种血管生成抑制剂的并发症中都可以看到这种疾病。先兆子痫的临床后果包括增加母体和胎儿并发症，而基于血管生成的癌症治疗的后果是对高效抗癌药物的剂量限制毒性。细胞外核苷酸（例如ATP及其水解产物腺苷）是确定内皮健康健康的重要因素。通常，细胞外ATP具有促炎和促血管性，而腺苷可防止炎症和血栓形成。细胞表面酶称为外核苷酸酶将细胞外ATP转化为腺苷，为血管内皮促进了稳定的环境。我们假设通过细胞表面腺苷受体的腺苷信号传导是VEGF缺乏环境中损伤的重要组成部分。在该提案的AIM 1中，我们将确定非选择性腺苷激动剂是否可以在VEGF缺乏症的小鼠中逆转蛋白尿和肾脏损伤。在AIM 2中，我们将确定特定的腺苷受体（A1，A2A，A2B或A3），该受体通过使用选择性腺苷激动剂和拮抗剂和拮抗剂和拮抗剂来介导腺苷对肾小球内皮的保护作用，从而在我们的小鼠模型中改善或肾脏损伤。这些研究将有助于定义介导VEGF缺乏状态的肾脏损伤的途径，还将确定药物治疗的特定靶标。已经开发了多种腺苷激动剂和拮抗剂，并在临床试验中进行了几项，因此可以考虑临床应用，而不会在长凳和床边长时间延迟。公共卫生相关性：在诸如前宾夕化或某些癌症疗法的并发症之类的疾病中，由于缺乏重要的生长因素而受伤。我们正在制定可能允许预防或逆转这种肾脏损伤的策略。我们的发现可能会减少严重的怀孕并发症，或者允许更有效地递送癌症化疗。