Assessment of MitoQ Therapy for Cold Preservation Renal Damage

MitoQ疗法对冷保存肾损伤的评估

• 批准号: 7995024
• 负责人: Kelvin G.M. Brockbank
• 金额: $ 18.96万
• 依托单位: CELL AND TISSUE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995024
• 关键词: 3-nitrotyrosine; Aconitate Hydratase; Animal Model; Animals; Antioxidants; Biochemistry; Biological Assay; Biological Preservation; Clinical; Complex; Control Groups; Crows; Cryopreservation; Data; Devices; Dialysis procedure; Dose; Effectiveness; End stage renal failure; Enzymes; Etiology; Evaluation; Family suidae; Generations; Glutathione S-Transferase; Goals; Grant; Hour; Human; In Situ Nick-End Labeling; Injury; Ischemia; Kidney; Kidney Transplantation; Laboratories; Lactate Dehydrogenase; Lead; Life; Mammals; Manganese Superoxide Dismutase; Marketing; Measures; Mediating; Medicare; Metabolic; Mitochondria; Modeling; Organ; Organ Donor; Organ Preservation; Organ Transplantation; Oxidants; Oxygen Consumption; Patient Selection; Patients; Peroxonitrite; Pharmaceutical Preparations; Phase; Production; Protocols documentation; Quality of life; Renal function; Reperfusion Therapy; Research; Rewarming; Rodent; Rodent Model; Small Business Innovation Research Grant; Solutions; Staining method; Stains; Superoxides; Technology; Testing; Therapeutic Intervention; Time; Tissues; Transplantation; University of Wisconsin-lactobionate solution; Waiting Lists; clinical application; cost; improved; mitoquinone; novel; pre-clinical; prevent; protective effect; public health relevance; renal ischemia; research study; respiratory; success; translational study

DESCRIPTION (provided by applicant): Renal transplantation has been a clinical reality for nearly 40 years. Transplantation is the only effective solution for organ end-stage renal failure. Long term renal function following transplantation has been shown to be better when kidneys are not subjected to cold preservation storage. However, despite the fact that cold preservation elicits significant kidney injury, cold preservation is essential for successful transplants today because it permits optimal patient selection and transport of kidneys derived from deceased donors. Cold preservation impacts both the quality of transplanted organs and the number of organs available for transplant. Therefore, therapeutic interventions that target the mechanisms by which kidneys are damaged by cold preservation could have a significant impact on the quality and availability of kidneys for transplant. We hypothesize that cold preservation induces mitochondrial damage, which leads to generation of superoxide and renal damage, and that inclusion of a novel mitochondrial antioxidant, MitoQ, preserves mitochondrial and renal function during cold preservation. Preliminary data in support of this hypothesis employing a rodent model are presented. The purpose of this proposal is to test the feasibility of decreasing oxidant production, mitochondrial and renal damage in two specific aims using a large animal porcine kidney model. In Specific Aim 1 oxidant production and renal damage will be compared in the presence of several doses of MitoQ, an inactive control compound, and a no treatment control group over a 48 hour cold preservation period. In Specific Aim 2 mitochondrial function 1 MitoQ will be investigated to determine whether or not there is a mitochondrial protective effect of MitoQ during renal cold preservation. It remains unknown whether cold renal preservation first induces mitochondrial damage which leads to oxidant damage or if oxidant damage causes mitochondrial damage. Feasibility for progression from this Phase I to a Phase II SBIR proposal will be determined by demonstration that the presence of MitoQ decreases oxidant production, renal damage and mitochondrial injury by 50% over untreated controls for at least 24 hours. Phase II would consist of translational studies to test the effectiveness of MitoQ therapy on post-transplantation renal function using the porcine autotransplantation model, as well as evaluation of the effect of adding MitoQ to human research kidneys ex vivo. PUBLIC HEALTH RELEVANCE: There is a significant kidney demand/supply imbalance, for example there were 16,520 kidney transplants in 2008 and there were 82,455 patients on the waiting list for kidneys on November 9th, 2009. Improving the quality and supply of kidneys would reduce the Medicare costs of patients otherwise on dialysis and improve patient quality of life. The costs of taking this technology to market are low because MitoQ is being developed for other, larger clinical applications and it is anticipated that the organ preservation application of MitoQ will be regulated as a device not a drug. This is because it is employed outside the body and the patient will not be exposed to it. MitoQ may also benefit other organ types used for transplantation, which are viable for much shorter times during cold preservation.

描述（由申请人提供）：肾移植已经成为临床现实近40年。移植是器官终末期肾功能衰竭唯一有效的解决方案。长期肾脏移植后的肾功能已被证明是更好的，当肾脏不受低温保存。然而，尽管冷保存会引起严重的肾脏损伤，但冷保存对于今天成功的移植是必不可少的，因为它允许最佳的患者选择和运输来自已故供者的肾脏。低温保存既影响移植器官的质量，也影响可供移植器官的数量。因此，针对肾脏因冷保存而受损的机制的治疗干预可能对移植肾脏的质量和可用性产生重大影响。我们假设低温保存诱导线粒体损伤，从而导致超氧化物和肾脏损伤，而包含一种新的线粒体抗氧化剂，MitoQ，在低温保存期间保持线粒体和肾脏功能。初步数据支持这一假设采用啮齿动物模型提出。本提案的目的是通过大型动物猪肾脏模型来测试在两个特定目标下减少氧化剂产生、线粒体和肾脏损伤的可行性。在特异性目的1中，将比较在不同剂量的MitoQ（一种无活性的对照化合物）和未处理的对照组在48小时的冷藏期中产生的氧化剂和肾脏损害。在Specific Aim 2线粒体功能1中，我们将对MitoQ进行研究，以确定MitoQ在肾脏冷保存过程中是否具有线粒体保护作用。冷肾保存首先引起线粒体损伤导致氧化损伤还是氧化损伤引起线粒体损伤尚不清楚。通过证明MitoQ的存在比未治疗的对照组至少减少了50%的氧化剂产生、肾脏损伤和线粒体损伤，将确定从I期进展到II期SBIR提案的可行性。II期将包括转化研究，使用猪自身移植模型测试MitoQ治疗对移植后肾功能的有效性，以及评估将MitoQ添加到人类研究肾脏的离体效果。

项目成果

MitoQ blunts mitochondrial and renal damage during cold preservation of porcine kidneys.

• DOI: 10.1371/journal.pone.0048590
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Parajuli N;Campbell LH;Marine A;Brockbank KG;Macmillan-Crow LA
• 通讯作者: Macmillan-Crow LA