Afferent arteriolar function and novel small molecules for renal radiation injury

入球小动脉功能和新型小分子治疗肾放射损伤

• 批准号: 8974351
• 负责人: NEIL S. MANDEL
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974351
• 关键词: Achievement; Acids; Advanced Development; Agonist; Anemia; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Antihypertensive Agents; Apoptotic; Arachidonic Acids; Attenuated; Azotemia; Biological Availability; Blood Pressure; Blood Vessels; Bone Marrow Transplantation; Captopril; Cardiovascular Diseases; Cells; Cisplatin; Clinical; Clinical Treatment; Complication; Cytochrome P450; Disease; Enzymes; Epoxide hydrolase; Event; Functional disorder; Generations; Genes; Goals; Gold; Health; Hypertension; Hypotension; Injury; Injury to Kidney; Kidney; Kidney Diseases; Kidney Failure; Lead; Malignant Neoplasms; Metabolic syndrome; Military Personnel; Modeling; Nephrology; Normal tissue morphology; Occupational Exposure; Organ; Pathway interactions; Prevention; Problem Solving; Radiation; Radiation Injuries; Radiation therapy; Radiobiology; Radionuclide therapy; Rattus; Regulation; Relaxation; Risk; Series; Testing; Time; Translating; Treatment Protocols; Tubular formation; Veterans; Whole-Body Irradiation; analog; arteriole; blood pressure reduction; cancer radiation therapy; chemotherapy; design; endothelial dysfunction; improved; inhibitor/antagonist; irradiation; kidney vascular structure; mimetics; mouse model; nephrotoxicity; novel; novel therapeutics; patient population; response; small molecule; targeted treatment; therapeutic target

DESCRIPTION (provided by applicant): Radiation nephropathy occurs after radiation therapies for cancer, and may also occur after accidental or belligerent radiation events. It is thus highly relevant to veterans with cancer and o those who had radiation injury from military occupational exposures. Current treatments are insufficient. We will test epoxyeicosatrienoic acid (EET) analogues as novel mitigators and treatment of radiation nephropathy. Radiation nephropathy causes endothelial injury, results in hypertension, parenchymal cell loss, and renal failure. We have developed epoxyeicosatrienoic acid (EET) analogs/mimetics that have endothelial-protective, anti-hypertensive, and anti-apoptotic actions that will be particularly beneficial in this patient population. We have shown that an EET analog dilates renal arterioles and lowers blood pressure in hypertensive rats and a mouse model of metabolic syndrome. We have also shown that these novel EET analogs protect the kidney from cisplatin-induced nephrotoxicity and hypertensive renal injury. We designed, synthesized, and screened a series of ~50 EET analogs and found two novel EET analogs that act when given orally. Vascular relaxation determined a ~1.5 M EC50 and a maximal response that was ~95% of that of 14,15-EET. The existing "gold standard" mitigator and treatment for radiation nephropathy is captopril, an angiotensin-converting-enzyme (ACE) inhibitor. Its benefit is incomplete. Better agents are needed for renal and other normal tissue radiation injuries. Our central hypothesis is that EETs have vascular protective activities that wil translate into a novel therapeutic for radiation nephropathy. The overall objective of this application is to determine the contribution of EETs to irradiation induced afferent arteriolar endothelial dysfunction and test the concept that increasing EETs will decrease vascular and kidney injury in an animal model of radiation nephropathy. Our long-term goal is establish orally available EET analogs as clinical treatments for radiation nephropathy, other normal tissue radiation injuries, and any cardiovascular disease involving arteriolar injury. We will test our central hypothesis by pursuing the following specific aims: Aim 1: Determine the time course of afferent arteriolar dysfunction and regulation of EETs following irradiation We hypothesize that afferent arteriolar dysfunction caused by decreased EETs precedes renal injury in an animal model of radiation nephropathy. Aim 2: Determine EET analogs ability to mitigate and treat radiation-induced renal injury We hypothesize that EET analogs will improve afferent arteriolar function through anti-apoptotic activity, will decrease blood pressure and will mitigate and treat radiation induced renal injury. Achievement of our aims will have an important positive impact because these will be a significant advance towards understanding the time course for and mechanism of renal injury following irradiation. The findings of these studies will be significant because they will advance the development of EET analog therapies for the mitigation and treatment of radiation nephropathy, other normal tissue radiation injuries, and any cardiovascular disease involving arteriolar injury.

描述（由申请人提供）： 放射性肾病发生在癌症放射治疗后，也可能发生在意外或敌对放射事件后。因此，它是高度相关的退伍军人与癌症和o那些谁有辐射损伤的军事职业照射。目前的治疗是不够的。我们将测试环氧二十碳三烯酸（EET）类似物作为新的缓解剂和治疗放射性肾病。放射性肾病引起内皮损伤，导致高血压、实质细胞丢失和肾衰竭。我们已经开发了具有内皮保护、抗高血压和抗凋亡作用的环氧二十碳三烯酸（EET）类似物/模拟物，其在该患者群体中将特别有益。我们已经证明，EET类似物扩张肾小动脉，降低高血压大鼠和代谢综合征小鼠模型的血压。我们还表明，这些新的EET类似物保护肾脏免受顺铂诱导的肾毒性和高血压肾损伤。我们设计、合成并筛选了一系列约50种EET类似物，发现了两种口服时起作用的新型EET类似物。血管舒张测定了约1.5 M EC 50和约为14，15-EET的95%的最大反应。现有的放射性肾病缓解和治疗的“金标准”是卡托普利，一种血管紧张素转换酶（ACE）抑制剂。它的好处是不完整的。肾脏和其他正常组织辐射损伤需要更好的药物。我们的中心假设是，依普利酮具有血管保护活性，这将转化为一种新的治疗放射性肾病的药物。本申请的总体目的是确定EkB对辐射诱导的传入小动脉内皮功能障碍的贡献，并在放射性肾病动物模型中测试增加EkB将减少血管和肾损伤的概念。我们的长期目标是建立口服EET类似物作为放射性肾病，其他正常组织辐射损伤和任何涉及小动脉损伤的心血管疾病的临床治疗。我们将通过追求以下具体目标来测试我们的中心假设：目标1：确定辐射后传入小动脉功能障碍和调节EkD的时间过程我们假设在放射性肾病动物模型中，由EkD降低引起的传入小动脉功能障碍先于肾损伤。目标二：确定EET类似物减轻和治疗辐射诱导的肾损伤的能力我们假设EET类似物将通过抗凋亡活性改善传入小动脉功能，将降低血压，并将减轻和治疗辐射诱导的肾损伤。我们的目标的实现将产生重要的积极影响，因为这将是一个重大的进步，了解照射后肾损伤的时间过程和机制。这些研究的结果将是重要的，因为它们将促进EET类似物疗法的发展，用于减轻和治疗放射性肾病、其他正常组织辐射损伤和任何涉及小动脉损伤的心血管疾病。