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：
8116507
负责人：
David J Friedman
金额：
$ 8.61万
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 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116507
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 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）：先兆子痫和用于治疗癌症的血管生成抑制剂是严重肾小球内皮损伤的两个常见原因。肾小球内皮依靠足细胞产生的血管内皮生长因子（VEGF）来维持内皮的稳定性和完整性。肾小球内皮细胞 VEGF 信号传导缺陷会导致内皮细胞增生症，这是一种内皮细胞功能障碍，临床上表现为蛋白尿和高血压。这种疾病既见于先兆子痫（由于可溶性受体阻断 VEGF 信号传导），也见于使用几种针对 VEGF 的血管生成抑制剂进行癌症治疗的并发症。先兆子痫的临床后果包括母体和胎儿并发症增加，而基于血管生成的癌症治疗的后果是高效抗癌药物的剂量限制性毒性。细胞外核苷酸（例如 ATP）及其水解产物腺苷是决定内皮健康的重要因素。一般来说，细胞外 ATP 具有促炎和促血栓形成的作用，而腺苷则可以防止炎症和血栓形成。称为核酸外切酶的细胞表面酶将细胞外 ATP 转化为腺苷，促进血管内皮细胞的稳定环境。我们假设，通过细胞表面腺苷受体的腺苷信号传导是 VEGF 缺乏时免受损伤的重要组成部分。在该提案的目标 1 中，我们将确定非选择性腺苷激动剂是否可以逆转 VEGF 缺乏小鼠的蛋白尿和肾损伤。在目标 2 中，我们将通过使用选择性腺苷激动剂和拮抗剂来鉴定介导腺苷对肾小球内皮的保护作用的特定腺苷受体（A1、A2a、A2b 或 A3），以改善或加重小鼠模型中的肾损伤。这些研究将有助于确定 VEGF 缺乏状态下介导肾损伤的途径，还将确定药物治疗的具体靶点。多种腺苷激动剂和拮抗剂已经被开发出来，其中几种处于临床试验阶段，因此可以考虑临床应用，而无需在实验室和临床之间拖延很长时间。公众健康相关性：在先兆子痫或某些癌症治疗的并发症等疾病中，肾脏会因缺乏重要的生长因子而受到损伤。我们正在制定可能预防或逆转这种肾损伤的策略。我们的研究结果可能会减少妊娠的严重并发症或允许更有效地进行癌症化疗。