Therapeutic Utility of renalase and renalase peptides in cisplatin-mediated renal

描述（由申请人提供）：顺铂是治疗多种癌症（包括睾丸癌、膀胱癌、卵巢癌和肺癌）的基础疗法。它还用于治疗儿童癌症。在所有情况下，急性肾损伤 (AKI) 的发生率都很高，这也可能导致 后期肾脏损害。这种风险限制了它的使用。我们在初步研究中发现，肾酶或肾酶的肽片段具有限制或治疗这种损伤的创新潜力，从而提高顺铂的安全性和实用性，并有可能带来更好的结果。 该提案将优先考虑最佳临床候选药物，用于后期开发和患者概念验证临床试验。肾酶是一种分泌型黄素腺嘌呤二核苷酸（FAD）依赖性胺氧化酶，由肾近曲小管合成，分泌于血液中，优先代谢肾上腺素，在基础状态下持续从尿中排出。我们已经证明肾酶缺乏（肾酶 KO 与野生型 [WT] 小鼠）与更严重的顺铂介导的急性和慢性肾损伤相关。最重要的是，给予重组肾酶可通过减少肾小管坏死、细胞凋亡和炎症标志物来改善小鼠 AKI。我们最近发现，与其酶特性无关，肾酶还可以激活受体介导的促生存信号级联，激活蛋白激酶 B (AKT)、下调 c-Jun N 末端激酶 (JNK) 并增加 Bcl-2 的表达。我们已经确定了肾酶蛋白介导与其同源受体相互作用的关键区域，并合成了几种完全模仿重组肾酶保护作用的肾酶肽。我们开发了顺铂介导的急性和慢性肾损伤的高度可重复的模型，以及敏感的方法（多光子显微镜）来测量管状肾小球（不参与肾小球滤过）的百分比并量化程度 CKD 中的肾纤维化。在拟议的研究中，我们将确定哪些肾酶分子（重组肾酶或肾酶肽）对于治疗小鼠顺铂 AKI 最为有效。我们将使用 AKI 的组织病理学、生化、炎症和功能标记来确定结果的优先级。我们将分析动物模型生物体液中拟议疗法的药物水平并将其与药理学结果关联起来，以帮助确定主要药物的优先顺序，并为最佳给药途径提供初步证据。

DESCRIPTION (provided by applicant): Cisplatin is a cornerstone therapy for a number of cancers including testicular, bladder, ovarian and lung. It is also used to treat cancers in children. In all cases there is a high incidence of acute kidney injury (AKI) that can also lead to later stage kidney damage. This risk limits its use. We have found in pilot studies that renalase, or peptide fragments of renalase, offers the innovative potential to limit or treat this damage, thereby improving the safety and utility of cisplatin and potentially resulting in better outcomes. This proposal will prioritize the best clinical candidate for later stage development and proof of concept clinical trials in patients. Renalase, a secreted flavin adenine dinucleotide (FAD) dependent amine oxidase, is synthesized by the renal proximal tubule, secreted in blood, preferentially metabolizes epinephrine, continuously excreted in urine in the basal state. We have shown renalase deficiency (renalase KO vs Wild type [WT] mice) is associated with dramatically more severe cisplatin-mediated acute and chronic renal injury. Most importantly, administration of recombinant renalase ameliorates AKI in mice by reducing renal tubular necrosis, apoptosis and markers of inflammation. We have recently discovered that, independent of its enzymatic properties, renalase also activates a receptor-mediated, pro-survival signaling cascade, with activation of protein kinase B (AKT), down- regulation of c-Jun N-terminal Kinase (JNK) and increased expression of Bcl-2. We have identified the critical regions of the renalase protein that mediate interaction with its cognate receptor, and synthesized several renalase peptides that fully mimic the protective effect of recombinant renalase. We have developed highly reproducible models of cisplatin-mediated acute and chronic kidney injury, and sensitive methods (multi-photon microscopy) to measure the percentage of atubular glomeruli (not contributing to glomeruli filtration) and quantify the extent renal fibrosis in CKD. In the proposed studies we will determine which renalase molecules (recombinant renalase or renalase peptides) are most effective in treating cisplatin AKI in mice. We will use histopathology, biochemical, inflammatory and functional markers of AKI to prioritize the results. We will analyze and correlate drug levels of the proposed therapies in biological fluids of the animal models with the pharmacologic results to aid in the lead drug prioritization and provide initial evidence for optimum routes of administration.