BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10294951
• 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/10294951
• 关键词: Address; 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; Journals; Kidney; Kidney Diseases; Legal patent; Lipids; Liver X Receptor; Mediating; Mediator of activation protein; 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 regulation; career; cost; drug development; epithelial Na+ channel; genetic approach; in vivo; inhibitor/antagonist; insulin sensitizing drugs; interest; lectures; lipid mediator; military veteran; mouse PGE synthase 1; mouse model; new therapeutic target; novel; preclinical evaluation; programs; receptor; site-1 protease; 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.

我一直在研究调节的前列腺素和其他脂质衍生的介体 肾功能很长时间。多年来，我们定义了考克斯的作用 2/mpges-1/pge2介导的前列腺素途径，核受体ppargamma 和肝X受体，以及肾脏健康和疾病中的硝基酸。我们最近的工作 已经证明了脂质介质和（Pro）肾素之间的重要相互作用 肾脏表明肾脏后，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。我们的结果 建议（Pro）肾素受体充当通用的下游途径 微调尿Na+和水排泄以及对血压的长期控制。这 开创性发现包括以下内容：1）PRR用prorenin激活，但不是 肾素刺激上皮Na+通道，2）PRR控制体内肾素活性，ENAC 收集管道中的Aquaporin-2表达，3）收集导管的缺失 导致糖尿病急症和aqoporine-2，4）可溶性PRR（SPRR）的下调 刺激肾含量2和尿液浓缩能力，5）Site-1蛋白酶 （S1P），但没有Furin或ADAM19有助于产生SPRR。在过去的5个 多年来，我们已经在高度著名的期刊上发表了22篇有关此主题的论文 PNA，JASN，高血压等。2016年，我被选为运送Lewis K. Dahl 奥兰多高血压理事会的纪念演讲。我的研究计划有 由校外补助金充分资助。在此报告期间，我收到了 多个NIH RO-1赠款和优异审查奖，总费用超过1000万美元。 已选择了续签申请的最新提交。 用于资金。我总共发表了161份同行评审的文章，并提供了更多 全世界的100次讲座。我们的工作与VA任务高度相关 大量退伍军人受到高血压和肾脏疾病的影响 据信哪个PRR扮演着重要角色，可以成为新的新目标 药物开发。重要的是，我的研究在该领域具有很高的翻译潜力 慢性肾脏疾病（CKD）和代谢疾病。我已经发展了多个 从临床前评估到II期临床试验的各个阶段的技术 这些疾病的治疗。到目前为止，我拥有5份专利，其中3项使用硝基化 酸用于治疗CKD和代谢疾病，1在类似的治疗中 使用SPRR。硝基酸技术已获得生物技术的Complecta，Inc的许可 成功完成了I氮气中多个I期临床试验的公司 酸（商业化为CXA-10），筹集了1亿美元，并推出了II期临床 2018年与CXA-10进行试验。与开发有关的第二种技术 重组可溶性PRR作为胰岛素敏化剂目前处于临床前 评估。 Novo Nordisk对这项技术表达了强烈的兴趣，并且是 执行内部验证。最近，我的RCS的中期进度报告是 额定评分为1.25，来自初级审稿人的评分为1.25，来自1.1的得分 中学评论者。