BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10618276
• 负责人: Tianxin Yang
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618276
• 关键词: Affect; Aldosterone; Angiotensin II; Antihypertensive Agents; Area; Award; Biochemical; Biotechnology; Chronic Kidney Failure; Clinical Treatment; Development; Diabetes Insipidus; Dinoprostone; Disease; Down-Regulation; Duct (organ) structure; Enzymes; Excretory function; Extramural Activities; Funding; Generations; Grant; Health; Hypertension; Inactive Renin; Inbred Dahl Rats; Infusion procedures; Insulin; Journals; Kidney; Kidney Diseases; Legal patent; Licensing; Lipids; Liver X Receptor; Mediating; Mediator; Metabolic Diseases; Mission; Nuclear Receptors; Oleic Acids; PPAR gamma; PTGS2 gene; Paper; Pathogenesis; Pathway interactions; Peer Review; Phase I Clinical Trials; Phase II Clinical Trials; Physiological; Play; Process; Progress Reports; Prostaglandins; Publishing; Recombinants; Renal function; Renin; Renin-Angiotensin System; Renin-Angiotensin-Aldosterone System; Reporting; Research; Role; Scientist; Seminal; Sodium Chloride; Technology; Therapeutic Uses; Time; United States National Institutes of Health; Urine; Validation; Veterans; WFDC2 gene; Water; Work; aquaporin-2; blood pressure control; career; commercialization; cost; drug development; epithelial Na+ channel; genetic approach; in vivo; inhibitor; interest; lectures; lipid mediator; military veteran; mouse PGE synthase 1; mouse model; new therapeutic target; novel; preclinical evaluation; programs; receptor; site-1 protease; translational potential; urinary

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.

我一直在研究前列腺素和其他调节脂质的介质 长期肾功能不全。多年来，我们定义了 COX 的作用- 2/mPGES-1/PGE2介导的前列腺素途径，核受体PPARgamma 和肝脏 X 受体，以及硝基油酸在肾脏健康和疾病中的作用。我们最近的工作 已证明脂质介质和肾素（原）之间存在重要的相互作用 受体介导的肾内肾素-血管紧张素系统 PRR和肾内肾素受COX-2/EP4途径的控制。我们的成果 表明肾素（原）受体是导致 微调尿钠和水的排泄以及长期控制血压。这 开创性的发现包括以下内容：1) 肾素原激活 PRR，但不激活 PRR 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在集合管中的表达，3)集合管PRR的缺失 导致尿崩症和 aqoporine-2, 4) 可溶性 PRR (sPRR) 下调 刺激肾水门蛋白 2 和尿液浓缩能力，以及 5) 位点 1 蛋白酶 (S1P) 但弗林蛋白酶或 ADAM19 有助于 sPRR 的产生。在过去的5年里 多年来，我们已在诸如 PNAS、JASN、高血压等。2016年，我被选为Lewis K. Dahl接生 在奥兰多高血压委员会举行的纪念演讲。我的研究计划有 得到了充足的外部补助金。本报告期内，我收到 多项 NIH RO-1 资助和一项优异评审奖，总成本超过 1000 万美元。 最近提交的优异奖续展申请已被选中 以获得资金。我总共发表了 161 篇同行评审文章，并发表了更多 在世界各地举办超过 100 场讲座。我们的工作与 VA 使命高度相关，因为 大量退伍军人患有高血压和肾病 PRR 被认为发挥着重要作用，并可能作为新的靶点 药物开发。重要的是，我的研究在这些领域具有很高的转化潜力 慢性肾脏病（CKD）和代谢性疾病。我开发了多个 从临床前评估到II期临床试验各个阶段的技术 治疗这些疾病。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 和代谢性疾病以及 1 类似的治疗 使用sPRR。硝基油酸技术已授权给生物技术公司Complexa, Inc 已成功完成硝基油酸多项I期临床试验的公司 酸（商品化名为CXA-10），融资1亿美元，启动II期临床 2018 年与 CXA-10 进行试验。第二种技术与开发 重组可溶性 PRR 作为胰岛素增敏剂目前正处于临床前阶段 评估。诺和诺德公司对此技术表示了浓厚的兴趣，并正在 执行内部验证。最近，我的 RCS 中期进度报告是 初级评审员评分为 1.25，评审员评分为 1.1，评价为优秀 二级审稿人。