BLR&D Research Career Scientist Award Application
BLR&D Research Career Scientist Award Application
批准号:
10294951
负责人:
Tianxin Yang
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-04-01 至 2027-03-31
关键词:
AddressAffectAldosteroneAngiotensin IIAntihypertensive AgentsAreaAwardBiochemicalBiotechnologyChronic Kidney FailureClinical TreatmentDevelopmentDiabetes InsipidusDinoprostoneDiseaseDown-RegulationDuct (organ) structureEnzymesExcretory functionExtramural ActivitiesFundingGenerationsGrantHealthHypertensionInactive ReninInbred Dahl RatsInfusion proceduresJournalsKidneyKidney DiseasesLegal patentLipidsLiver X ReceptorMediatingMediator of activation proteinMetabolic DiseasesMissionNuclear ReceptorsOleic AcidsPPAR gammaPTGS2 genePaperPathogenesisPathway interactionsPeer ReviewPhase I Clinical TrialsPhase II Clinical TrialsPhysiologicalPlayProcessProgress ReportsProstaglandinsPublishingRecombinantsRenal functionReninRenin-Angiotensin SystemRenin-Angiotensin-Aldosterone SystemReportingResearchRoleScientistSeminalSodium ChlorideTechnologyTherapeutic UsesTimeUnited States National Institutes of HealthUrineValidationVeteransWFDC2 geneWaterWorkaquaporin-2blood pressure regulationcareercostdrug developmentepithelial Na+ channelgenetic approachin vivoinhibitor/antagonistinsulin sensitizing drugsinterestlectureslipid mediatormilitary veteranmouse PGE synthase 1mouse modelnew therapeutic targetnovelpreclinical evaluationprogramsreceptorsite-1 proteaseurinary
中文摘要
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
微调尿钠和水分排泄,长期控制血压。这个
开创性的发现包括:1)Prorenin激活PRR,但不是
肾素刺激上皮细胞钠通道,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
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。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Adipose-derived sPRR controls circadian rhythm of blood pressure through inhibition of renal NCC activity
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批准号:10522511
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项目类别:
-
资助金额:$63.07万
-
财政年份:2022
-
负责人:Tianxin Yang
-
依托单位:
Adipose-derived sPRR controls circadian rhythm of blood pressure through inhibition of renal NCC activity
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批准号:10636885
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项目类别:
-
资助金额:$58.66万
-
财政年份:2022
-
负责人:Tianxin Yang
-
依托单位:
Defining renal S1P/sPRR/AT1R pathway in salt-sensitive hypertension
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批准号:10293534
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项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Tianxin Yang
-
依托单位:
BLR&D Research Career Scientist Award Application
-
批准号:9995217
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Tianxin Yang
-
依托单位:
Defining renal S1P/sPRR/AT1R pathway in salt-sensitive hypertension
-
批准号:10514577
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Tianxin Yang
-
依托单位:
BLR&D Research Career Scientist Award Application
-
批准号:10618276
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Tianxin Yang
-
依托单位:
BLR&D Research Career Scientist Award Application
-
批准号:10454237
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Tianxin Yang
-
依托单位:
Defining renal S1P/sPRR/AT1R pathway in salt-sensitive hypertension
-
批准号:9888044
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项目类别:
-
资助金额:$0.0万
-
财政年份:2020
-
负责人:Tianxin Yang
-
依托单位:
Role of (pro)renin receptor in aldosterone signaling in the kidney
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批准号:9921471
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项目类别:
-
资助金额:$52.84万
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财政年份:2018
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负责人:Tianxin Yang
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依托单位:
Interaction of (pro)renin receptor and PPARy in regulation of plasma volume
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批准号:9729034
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项目类别:
-
资助金额:$57.55万
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财政年份:2017
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负责人:Tianxin Yang
-
依托单位:
Interaction of (pro)renin receptor and PPARy in regulation of plasma volume
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批准号:9389982
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项目类别:
-
资助金额:$57.18万
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财政年份:2017
-
负责人:Tianxin Yang
-
依托单位:
Interaction of (pro)renin receptor and PPARy in regulation of plasma volume
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批准号:10246248
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项目类别:
-
资助金额:$57.55万
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财政年份:2017
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负责人:Tianxin Yang
-
依托单位:
Interaction of PGE2 and intrarenal RAS in AngII-induced hypertension
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批准号:9016549
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项目类别:
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资助金额:$41.33万
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财政年份:2015
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负责人:Tianxin Yang
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依托单位:
Interaction of PGE2 and intrarenal RAS in AngII-induced hypertension
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批准号:9242018
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项目类别:
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资助金额:$41.33万
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财政年份:2015
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负责人:Tianxin Yang
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依托单位:
Control of collecting duct function by lipid-derived factors in obesity
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批准号:9107860
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项目类别:
-
资助金额:$32.41万
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财政年份:2013
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负责人:Tianxin Yang
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依托单位:
Control of collecting duct function by lipid-derived factors in obesity
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批准号:8720755
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项目类别:
-
资助金额:$32.41万
-
财政年份:2013
-
负责人:Tianxin Yang
-
依托单位:
Control of collecting duct function by lipid-derived factors in obesity
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批准号:9282530
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项目类别:
-
资助金额:$32.41万
-
财政年份:2013
-
负责人:Tianxin Yang
-
依托单位:
Control of collecting duct function by lipid-derived factors in obesity
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批准号:8504453
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项目类别:
-
资助金额:$30.28万
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财政年份:2013
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负责人:Tianxin Yang
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依托单位:
mPGES-1/EP1 in volume regulation
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批准号:8282608
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项目类别:
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资助金额:$0.0万
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财政年份:2011
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负责人:Tianxin Yang
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依托单位:
mPGES-1/EP1 in volume regulation
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批准号:8398952
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项目类别:
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资助金额:$0.0万
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财政年份:2011
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负责人:Tianxin Yang
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依托单位:
海外基金