Role of Estrogen Related Receptors in Age Related Kidney Disease
雌激素相关受体在年龄相关性肾脏疾病中的作用
基本信息
- 批准号:10320972
- 负责人:
- 金额:$ 47.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-12-21 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Renal Failure with Renal Papillary NecrosisAge-MonthsAgingAgonistAlbuminsBile AcidsCaloric RestrictionCell AgingCellsChronic Kidney FailureElderlyExcretory functionFemaleFibrosisFolic AcidG-Protein-Coupled ReceptorsGPBAR1 geneGTP-Binding Protein alpha Subunits, GsGenerationsHumanHypertensionImageImpairmentInflammationInflammatoryInflammatory ResponseInjury to KidneyIschemiaKidneyKidney DiseasesKnockout MiceKnowledgeLabelLifeMediatingMetabolic syndromeMicroscopeMicroscopyMitochondriaModelingMonitorMusNuclear Hormone ReceptorsOrganPersonsPopulationPrevention strategyRecoveryRegulationRenal functionRenal tubule structureReperfusion TherapyResolutionRoleSignal PathwaySignal TransductionStimulator of Interferon GenesTNF geneTestingThree-Dimensional ImagingTransforming Growth Factor betaTubular formationadeno-associated viral vectorage groupage relatedcomorbiditycytokineestrogen-related receptorfarnesoid X-activated receptorhuman old age (65+)improvedinhibitorkidney fibrosismalemicroscopic imagingmitochondrial dysfunctionnovelpreventresponsesecond harmonicsenescencetreatment strategyurinary
项目摘要
The proposed studies will test the hypothesis that mitochondrial dysfunction and increased inflammation
mediates age-related kidney disease. We propose that increased expression of estrogen related receptors ERRα
and ERRγ improves mitochondrial function, and decreases cGAS-STING signaling, cellular senescence and
inflammation, which reverses age-related kidney disease. In addition, the effects of ERRs on senescence,
inflammation, and fibrosis are cGAS-STING dependent. Furthermore, increased expression of ERRα and ERRγ
or inhibition of cGAS-STING signaling prevents acute kidney injury mediated by folic acid, LPS, or
ischemia/reperfusion
In SPECIFIC AIM 1 we will test the hypothesis that increased renal tubular ERRα or ERRγ will improve
mitochondrial function and inflammation and reverse age-related kidney disease. We will determine: A)
the effects of renal tubular ERRα or ERRγ or simultaneous ERRα/ERRγ increased expression on kidney
mitochondrial function, inflammation and kidney disease; B) if renal tubular increases in ERRs prevents acute
kidney injury mediated by a) folic acid, b) LPS, or c) ischemia/reperfusion. The rationale for these studies is that
all three models result in decreased ERRα and ERRγ expression in the kidneys; C) direct effects of increased
expression of ERRα, ERRγ, or simultaneous ERRα and ERRγ in human proximal tubular cells.
In SPECIFIC AIM 2 we will test the hypothesis that the effects of ERRα or ERRγ to reverse inflammation
and kidney disease in aging are mediated via a cGAS-STING dependent mechanism. We will determine
the roles of A) cGAS: generalized or kidney specific cGAS knockout mice treated with ERR; B) STING:
generalized or kidney specific STING knockout mice treated with ERR; C) We will determine if treatment of mice
with STING inhibitor prevents acute kidney injury mediated by a) folic acid, b) LPS, or c) ischemia/reperfusion.
The rationale for these studies is that all three models result in increased cGAS-STING expression in the kidneys.
INNOVATION: 1) These studies will determine if inducible increased expression of ERR-α and ERR-γ in the
renal tubules will improve mitochondrial dysfunction, cGAS-STING mediated inflammation and age-related
kidney disease. 2) While the effects of ERRs in regulation of mitochondrial function has been studied, mainly in
other target organs, the effects of ERRs in regulation of inflammation is novel and has not been studied in the
kidney. To this end we will perform mechanistic studies to determine the role of cGAS-STING in regulating
inflammation and the effects of ERR in the kidney.
拟议中的研究将测试线粒体功能障碍和炎症增加的假设,
介导与年龄相关的肾病。我们认为雌激素相关受体ERRα的表达增加
和ERRγ改善线粒体功能,并减少cGAS-STING信号传导,细胞衰老和
炎症,逆转与年龄相关的肾脏疾病。此外,ERRs对衰老的影响,
炎症和纤维化是cGAS-STING依赖性的。此外,ERRα和ERRγ的表达增加,
或抑制cGAS-STING信号传导防止由叶酸、LPS或
缺血/再灌注
在特定目的1中,我们将检验肾小管ERRα或ERRγ增加将改善
线粒体功能和炎症以及逆转与年龄相关的肾脏疾病。我们将确定:A)
肾小管ERRα或ERRγ或同时ERRα/ERRγ表达增加对肾脏的影响
B)如果肾小管增加,则ERRs阻止急性
由a)叶酸,B)LPS,或c)缺血/再灌注介导的肾损伤。这些研究的基本原理是,
所有三种模型均导致肾脏中ERRα和ERRγ表达降低; C)增加的直接作用
人近端肾小管细胞中ERRα、ERRγ或同时ERRα和ERRγ的表达。
在《特异性目的2》中,我们将检验ERRα或ERRγ逆转炎症的作用的假设。
和肾脏疾病是通过cGAS-STING依赖性机制介导的。我们将确定
A)cGAS:用ERR处理的全身性或肾特异性cGAS敲除小鼠; B)STING:
C)我们将确定用ERR治疗的小鼠是否为全身性或肾特异性STING敲除小鼠;
与STING抑制剂联合使用可预防由a)叶酸、B)LPS或c)缺血/再灌注介导的急性肾损伤。
这些研究的基本原理是,所有三种模型都导致肾脏中cGAS-STING表达增加。
创新:1)这些研究将确定是否诱导性增加ERR-α和ERR-γ的表达,
肾小管将改善线粒体功能障碍,cGAS-STING介导的炎症和年龄相关的
肾病2)虽然已经研究了ERRs在调节线粒体功能中的作用,主要是在
在其他靶器官中,ERRs在炎症调节中的作用是新的,并且尚未在本领域中研究。
肾为此,我们将进行机制研究,以确定cGAS-STING在调节细胞凋亡中的作用。
炎症和ERR在肾脏中的作用。
项目成果
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MOSHE LEVI其他文献
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{{ truncateString('MOSHE LEVI', 18)}}的其他基金
Role of Estrogen Related Receptors in Age Related Kidney Disease
雌激素相关受体在年龄相关性肾脏疾病中的作用
- 批准号:
10154246 - 财政年份:2020
- 资助金额:
$ 47.95万 - 项目类别:
Role of Estrogen Related Receptors in Age Related Kidney Disease
雌激素相关受体在年龄相关性肾脏疾病中的作用
- 批准号:
10535466 - 财政年份:2020
- 资助金额:
$ 47.95万 - 项目类别:
Role of FXR and TGR5 in Age Related Renal Diseases
FXR 和 TGR5 在年龄相关性肾脏疾病中的作用
- 批准号:
8984793 - 财政年份:2016
- 资助金额:
$ 47.95万 - 项目类别:
Role of FXR and TGR5 in Age Related Renal Diseases
FXR 和 TGR5 在年龄相关性肾脏疾病中的作用
- 批准号:
9346676 - 财政年份:2016
- 资助金额:
$ 47.95万 - 项目类别:
Non-Invasive Evaluation of Transplant Kidney using OCT
使用 OCT 对移植肾进行无创评估
- 批准号:
9259961 - 财政年份:2014
- 资助金额:
$ 47.95万 - 项目类别:
Treatment of Kidney Disease in Diabetes and Obesity
糖尿病和肥胖症肾病的治疗
- 批准号:
8743204 - 财政年份:2013
- 资助金额:
$ 47.95万 - 项目类别:
Treatment of Kidney Disease in Diabetes and Obesity
糖尿病和肥胖症肾病的治疗
- 批准号:
9140010 - 财政年份:2013
- 资助金额:
$ 47.95万 - 项目类别: