Low-dose irradiation as a novel intervention for diabetic nephropathy

低剂量照射作为糖尿病肾病的新型干预措施

• 批准号: 8731866
• 负责人: Lu Cai
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731866
• 关键词: Adverse effects; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptotic; Biological; Cell Death; Cell Nucleus; Cell Proliferation; Complications of Diabetes Mellitus; Cytogenetics; Cytosol; Data; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease; Dose; Drug Combinations; Drug Targeting; Drug usage; Frequencies; Genes; Germ Cells; Glycogen Synthase Kinase 3; Goals; Harvest; In Vitro; Inflammation; Intervention; Kidney; Kidney Diseases; Kidney Failure; Low Dose Radiation; Mediating; Methods; Modality; Modeling; Mus; Organ; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Prevention; Preventive; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Proto-Oncogenes; Radiation; Radiation therapy; Reactive Oxygen Species; Renal function; Renin-Angiotensin System; Risk; Rodent; Role; Safety; Streptozocin; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Up-Regulation; Work; cytotoxic; diabetic; diabetic patient; in vivo; innovation; irradiation; mouse model; novel; novel strategies; novel therapeutic intervention; nuclear factor-erythroid 2; oxidative damage; prevent; public health relevance; repaired; response; safety testing; tool; transcription factor

DESCRIPTION (provided by applicant): The goal of this study is to develop low-dose radiation (LDR) as a new tool to prevent and treat diabetic nephropathy. Currently no effective preventive or therapeutic approaches are available to treat diabetic nephropathy, which is the most common cause of renal failure. We have been investigating the biological effects of LDR, including its hormesis and adaptive response, in vitro and in vivo. A major advantage of LDR is that it activates many genes in antioxidant and anti-inflammatory pathways, rather than just single protective gene, potentially making LDR a very potent and novel therapeutic approach. This was borne out by our preliminary studies that show that LDR at 25 mGy decreases diabetic nephropathy, by significantly reducing diabetes-induced renal oxidative damage and inflammation. Our latest preliminary data show up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and protein kinase B (also called Akt) phosphorylation in the kidney of diabetic mice, also exposed to LDR at 25 mGy. NRF2 is a transcription factor involved in expression of a broad range of protective genes. Therefore our central hypothesis is that exposure of diabetic animals to LDR can prevent and treat diabetic nephropathy by activation of many protective genes through stimulation of the Nrf2 pathway. This hypothesis will be tested through three specific Aims: (1) LDR at the optimal condition not only prevents, but also delay diabetic nephropathy; (2) the optimal LDR is safe for diabetic subjects; (3) the renal protection by the optimal LDR is predominantly mediated by up- regulating Nrf2-mediated multiple antioxidant components. The great advantage of LDR is that it offers a highly controllable, non-invasive method for eliciting endogenous, synergistic tissue protection and repair mechanisms. This innovative approach will be particularly valuable for the diabetic patient who already has significantly decreased renal function that increases the toxicity of invasive drugs. Therefore, this project will open a new avenue for the prevention and treatment of diabetic complications.

描述（由申请人提供）： 本研究的目的是开发低剂量辐射（LDR）作为预防和治疗糖尿病肾病的新工具。目前没有有效的预防或治疗方法可用于治疗糖尿病肾病，这是肾衰竭的最常见原因。我们一直在体外研究低剂量辐射的生物学效应，包括它的兴奋效应和适应性反应 和体内。LDR的一个主要优点是它激活了抗氧化和抗炎途径中的许多基因，而不仅仅是单个保护基因，这可能使LDR成为一种非常有效和新颖的治疗方法。我们的初步研究证实了这一点，表明25 mGy的LDR通过显著减少糖尿病诱导的肾氧化损伤和炎症来降低糖尿病肾病。我们最新的初步数据显示，也暴露于25 mGy LDR的糖尿病小鼠肾脏中核因子红细胞2相关因子2（Nrf 2）表达和蛋白激酶B（也称为Akt）磷酸化上调。NRF 2是一种转录因子，参与多种保护性基因的表达。因此，我们的中心假设是糖尿病动物暴露于LDR可以通过刺激Nrf 2通路激活许多保护性基因来预防和治疗糖尿病肾病。 该假设将通过三个特定目的进行测试：（1）在最佳条件下的LDR不仅预防而且延迟糖尿病肾病;（2）最佳LDR对于糖尿病受试者是安全的;（3）最佳LDR的肾保护主要通过上调Nrf 2介导的多种抗氧化剂组分来介导。 LDR的巨大优势在于它提供了一种高度可控的非侵入性方法，用于引发内源性协同组织保护和修复机制。这种创新的方法将是特别有价值的糖尿病患者谁已经显着降低肾功能，增加毒性 侵入性药物。因此，该项目将为糖尿病并发症的预防和治疗开辟一条新的途径。