BLR&D Research Career Scientist Award Application

我一直在研究芦荟素和其他脂质衍生的介质， 肾功能长期多年来，我们已经定义了考克斯的作用- 2/mPGES-1/PGE 2介导的前列腺素途径，核受体PPARgamma 和肝脏X受体，以及肾脏健康和疾病中的硝基油酸。我们最近的工作 已经证明了脂质介质和（原）肾素之间的重要相互作用 受体介导的肾内肾素-血管紧张素系统， PRR和肾内肾素受考克斯-2/EP 4通路的调控。我们的结果 表明（原）肾素受体作为一种常见下游途径， 微调尿Na+和水排泄以及长期控制血压。的 开创性的发现包括以下：1）用前肾素激活PRR，但不 肾素刺激上皮Na+通道，2）PRR控制体内肾素活性，ENaC 和水通道蛋白-2表达; 3）集合管PRR缺失 导致尿崩症和水溶性PRR（sPRR）下调 刺激肾水孔蛋白-2和尿浓缩能力，和5）位点-1蛋白酶 (S1P)而不是弗林蛋白酶或ADAM 19有助于sPRR的产生。过去5 多年来，我们已经发表了22篇关于这一主题的论文，在高度负盛名的期刊，如 PNAS、JEFFECT、Hypertension等，2016年，我被选中为刘易斯K.达尔 在奥兰多高血压理事会的纪念演讲。我的研究计划 得到了校外赠款在本报告所述期间，我收到了 多个NIH RO-1赠款和一个总成本超过1000万美元的优秀评审奖。 近期提交的优异奖延续申请已入选 资金。我总共发表了161篇同行评议的文章， 在世界各地举办了超过100场讲座。我们的工作与VA使命高度相关， 大量退伍军人受到高血压和肾病的影响， PRR被认为发挥了重要作用，并可能作为新的靶点， 药物开发重要的是，我的研究在以下领域具有很高的转化潜力： 慢性肾脏病（CKD）和代谢性疾病。我开发了多种 从临床前评估到II期临床试验的各个阶段， 这些疾病的治疗。到目前为止，我拥有5项专利，其中3项是关于硝基油酸的使用 酸用于治疗CKD和代谢性疾病和1对类似的治疗 使用sPRR。硝基油酸技术被授权给Complexa，Inc，一家生物技术公司， 该公司已成功完成多项硝基油酸I期临床试验 酸（商品化为CXA-10），筹集了1亿美元，并启动了II期临床试验。 2018年使用CXA-10进行试验。第二种技术涉及一种 作为胰岛素增敏剂的重组可溶性PRR目前处于临床前研究阶段， 评价诺和诺德对这项技术表示了浓厚的兴趣， 进行内部验证。最近，我的RCS的中期进度报告是 被评为优秀，主要评审员评分为1.25， 二级审查员。

I have been studying prostaglandins and other lipid-derived mediators that regulate renal function for a long time. Over the years, we have defined the role of COX- 2/mPGES-1/PGE2-mediated prostaglandin pathway, nuclear receptors PPARgamma and liver X receptor, and nitro-oleic acid in renal health and disease. Our recent work has demonstrated an important interplay between the lipid mediators and (pro)renin receptor-mediated intrarenal renin-angiotensin system after the demonstration that renal PRR and intrarenal renin are under the control of COX-2/EP4 pathway. Our results suggest that (pro)renin receptor serves as a common downstream pathway leading to fine-tuning urinary Na+ and water excretion and long-term control of blood pressure. The seminal discoveries include the following: 1) activation of PRR with prorenin but not renin stimulates epithelial Na+ channel, 2) PRR controls the in vivo renin activity, ENaC and aquaporin- 2 expression in the collecting duct, 3) deletion of collecting duct PRR results in diabetes insipidus and downregulation of aqoporine-2, 4) soluble PRR (sPRR) stimulates renal aquoporine-2 and urine concentrating capability, and 5) site-1 protease (S1P) but not furin or ADAM19 contributes to the generation of sPRR. During the past 5 years, we have published 22 papers on this topic in highly prestigious journals such as PNAS, JASN, Hypertension, etc. In 2016, I was selected to deliver Lewis K. Dahl Memorial Lecture at the Council on Hypertension in Orlando. My research program has been well funded by extramural grants. During this reporting period, I have received multiple NIH RO-1 grants and a Merit Review Award with total costs exceeding $10M. The recent submission of the renewal application of the Merit Award has been selected for funding. I have published a total of 161 peer-reviewed articles and delivered more than 100 lectures all over the world. Our work is highly relevant to the VA mission since a significant number of veterans are affected by hypertension and renal disease for which PRR is believed to play a major role and may serve as a novel target for new drug development. Importantly, my research has high translational potential in the areas of chronic kidney disease (CKD) and metabolic disease. I have developed multiple technologies at various stages from preclinical evaluation to Phase II clinical trial for treatment of these diseases. So far, I holds 5 patents with 3 on the use of nitro-oleic acid for the treatment of CKD and metabolic disease and 1 on the similar therapeutic use of sPRR. The nitro-oleic acid technology was licensed to Complexa, Inc, a biotech company that has successfully completed multiple Phase I clinical trials on nitro-oleic acid (commercialized as CXA-10), raised $100 million, and launched a Phase II clinical trial with CXA-10 in 2018. A second technology related to the development of a recombinant soluble PRR as an insulin-sensitizing agent is currently under preclinical evaluation. Novo Nordisk has expressed strong interest in this technology and is performing internal validations. Recently, the mid-term progress report for my RCS was rated excellent with the scores of 1.25 from primary reviewer and 1.1 from the secondary reviewer.