BLR&D Research Career Scientist Award Application

BLR

• 批准号: 9995217
• 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/9995217
• 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.

我一直在研究前列腺素和其他调节 肾功能损害时间较长。多年来，我们已经定义了考克斯的角色- 2/mPGES-1/PGE2介导的前列腺素途径、核受体PPAR-γ 和肝脏X受体，以及硝基油酸与肾脏健康和疾病。我们最近的工作 已经证明了脂质介体和肾素原之间的重要相互作用 受体介导的肾素-血管紧张素系统证实肾脏 PRR和肾内肾素受COX-2/EP4途径控制。我们的结果 提示(PRO)肾素受体是一条共同的下游通路，导致 微调尿Na+和水分排泄，长期控制血压。这个 开创性的发现包括：1)Prorenin激活PRR，但不是 肾素刺激上皮细胞Na+通道，2)PRR控制体内肾素活性 和水通道蛋白-2在集合管中的表达，3)集合管PRR的缺失 尿崩症和Aqopine-2，4)可溶性PRR(SPRR)下调的结果 刺激肾脏水通道蛋白-2和尿液浓缩能力，以及5)部位-1蛋白酶 (S1P)而不是呋喃或ADAM19对sPRR的产生有贡献。在过去5年内 多年来，我们在著名期刊上发表了22篇关于这一主题的论文，如 PNAS、JASN、高血压等。2016年，我被选为刘易斯·K·达尔 在奥兰多高血压委员会的纪念讲座。我的研究项目已经 由校外赠款提供了充足的资金。在本报告所述期间，我收到了 多项NIH RO-1拨款和一项功绩审查奖，总成本超过1000万美元。 最近提交的荣誉奖续展申请已被选中 为了资金。我总共发表了161篇同行评议的文章，并发表了更多 在世界各地举办100多场讲座。我们的工作与退伍军人管理局的任务高度相关，因为 相当数量的退伍军人患有高血压和肾脏疾病 其中PRR被认为发挥了重要作用，并可能成为新的 药物开发。重要的是，我的研究在这些领域具有很高的翻译潜力 慢性肾脏疾病(CKD)和代谢性疾病。我已经开发出多个 从临床前评估到第二阶段临床试验的不同阶段的技术 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 ACID用于治疗CKD和代谢性疾病，1例用于类似治疗 使用sPRR。硝基油酸技术被授权给生物技术公司Complexa，Inc. 成功完成多项硝基油酸I期临床试验的公司 ACID(商业化名称为CXA-10)，筹集了1亿美元，并启动了第二阶段临床 2018年试用CXA-10。第二项技术涉及开发一种 重组可溶性PRR作为胰岛素增敏剂目前处于临床前阶段 评估。诺和诺德已经表达了对这项技术的强烈兴趣，并正在 正在执行内部验证。最近，我的RCS的中期进度报告是 评为优秀，主要评审员的评分为1.25分， 二次审查员。