Renal Protective Effects of Circulating Angiopoietin-like-4
循环血管生成素样 4 的肾脏保护作用
基本信息
- 批准号:9002042
- 负责人:
- 金额:$ 31.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-03-10 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:ANGPTL4 geneAdipose tissueAffectAlbuminsBeta-N-AcetylglucosaminidaseBindingBinding ProteinsBuffaloesCharacteristicsChronic Kidney FailureDevelopmentDiabetic NephropathyDiseaseEnd stage renal failureEndothelial CellsEndotheliumFamilyFatty AcidsFeedbackFocal Segmental GlomerulosclerosisGene ExpressionGene TargetingGlomerular CapillaryGlycoproteinsGoalsHealthHeartHigh Density LipoproteinsHumanHydrogen PeroxideHydrolysisHyperlipidemiaHypertriglyceridemiaHypoalbuminemiaIntegrinsKidneyKnockout MiceLaboratoriesLinkLiverMedicineModelingModificationMolecularMusMutationNatureNephrotic SyndromeNon-Insulin-Dependent Diabetes MellitusNonesterified Fatty AcidsOrganPathogenesisPathway interactionsPatientsPeripheralPeroxisome Proliferator-Activated ReceptorsPlasmaPlasma AlbuminProcessProteinsProteinuriaRattusRecombinantsRenal glomerular diseaseRenin-Angiotensin SystemRoleSeveritiesSiteSkeletal MuscleTestingTherapeuticTherapeutic AgentsTransgenic OrganismsTriglyceridesUnited StatesUp-Regulationbasediabeticglomerular endotheliumglomerulosclerosislipoprotein lipasemutantnoveloverexpressionpodocyteprotective effectsocialstandard of careuptakeurinary
项目摘要
DESCRIPTION (provided by applicant): Reducing proteinuria slows the progression of chronic kidney disease. The current standard of care is to block of the renin - angiotensin system at various levels to reduce proteinuria. However, reduction of proteinuria is often incomplete, since other pathways involved in the pathogenesis or modification of proteinuria are not affected by this therapy. The long term goal of the PI's lab is to develop novel mechanism - based therapeutic agents that will reduce proteinuria and reduce the progression of chronic kidney disease due to glomerular disorders. Reducing the progression of chronic kidney disease to end stage kidney disease will have a major positive social and financial impact in the United States and worldwide. The PI's laboratory has discovered a major role of the circulating glycoprotein Angiopoietin-like-4 (Angptl4) in human and experimental nephrotic syndrome. Studies conducted by his team show that circulating Angptl4 is the first molecular link between proteinuria, hypoalbuminemia and hypertriglyceridemia, three major components of nephrotic syndrome. In glomerular disease, increased Angptl4 secretion from skeletal muscle, heart, liver and adipose tissue occurs when proteinuria becomes moderate to severe (in the human context, when it reaches nephrotic range). Circulating Angptl4 reduces proteinuria by binding to glomerular endothelial αvß5 integrin, while also inducing hypertriglyceridemia by inhibiting the activity of endothelium bound lipoprotein lipase. Further, it appears that this multi-organ upregulation of Angptl4 expression results from an increase in the plasma free fatty acid / albumin ratio. The PI has developed four new mutant forms of human Angptl4 protein that reduce proteinuria in rat models of focal and segmental glomerulosclerosis (FSGS) and diabetic nephropathy without significantly affecting plasma triglyceride levels. In Specific Aim 1, the relationship between elevated plasma free fatty acid / albumin ratio with increased peripheral organ Angptl4 expression in nephrotic syndrome will be investigated further using organ specific PPAR knockout mice. In Specific Aim 2, we will test whether administration of mutant human Angptl4 twice every month, or transgenic expression of rat Angptl4 from adipose tissue can reduce glomerulosclerosis and progression of chronic kidney disease in rats models of FSGS or diabetic nephropathy. In Specific Aim 3, mechanisms by which the interaction of circulating Angptl4 with glomerular endothelial αvß5 integrin reduces proteinuria will be investigated.
描述(由申请人提供):减少蛋白尿减缓慢性肾脏疾病的进展。目前的标准治疗是阻断不同水平的肾素-血管紧张素系统以减少蛋白尿。然而,蛋白尿的减少通常是不完全的,因为参与蛋白尿发病机制或改变的其他途径不受这种治疗的影响。PI实验室的长期目标是开发新的基于机制的治疗药物,以减少蛋白尿并减少肾小球疾病引起的慢性肾脏疾病的进展。减少慢性肾脏疾病向终末期肾脏疾病的进展将在美国和世界范围内产生重大的积极社会和经济影响。PI的实验室已经发现循环糖蛋白血管生成素样-4(Angptl 4)在人类和实验性肾病综合征中的主要作用。他的团队进行的研究表明,循环Angptl 4是蛋白尿、低白蛋白血症和高胆固醇血症(肾病综合征的三个主要组成部分)之间的第一个分子联系。在肾小球疾病中,当蛋白尿变得中度至重度时(在人类背景下,当其达到肾病范围时),骨骼肌、心脏、肝脏和脂肪组织的Angptl 4分泌增加。循环Angptl 4通过结合肾小球内皮α v β 5整联蛋白减少蛋白尿,同时还通过抑制内皮结合脂蛋白脂酶的活性诱导高脂血症。此外,似乎Angptl 4表达的这种多器官上调是由血浆游离脂肪酸/白蛋白比率的增加引起的。PI已经开发了四种新的突变形式的人Angptl 4蛋白,其在局灶性和节段性肾小球硬化(FSGS)和糖尿病肾病的大鼠模型中减少蛋白尿,而不显著影响血浆甘油三酯水平。在具体目标1中,将使用器官特异性PPAR敲除小鼠进一步研究肾病综合征中升高的血浆游离脂肪酸/白蛋白比率与增加的外周器官Angptl 4表达之间的关系。在具体目标2中,我们将测试在FSGS或糖尿病肾病的大鼠模型中,每月两次施用突变的人Angptl 4或从脂肪组织转基因表达大鼠Angptl 4是否可以减少肾小球硬化和慢性肾病的进展。在具体目标3中,将研究循环Angpt 14与肾小球内皮α v β 5整联蛋白的相互作用减少蛋白尿的机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Sumant Singh Chugh其他文献
Sumant Singh Chugh的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Sumant Singh Chugh', 18)}}的其他基金
Investigation of non-HIV Collapsing Glomerulopathy
非 HIV 塌陷性肾小球病的调查
- 批准号:
9750079 - 财政年份:2016
- 资助金额:
$ 31.97万 - 项目类别:
Renal Protective Effects of Circulating Angiopoietin-like-4
循环血管生成素样 4 的肾脏保护作用
- 批准号:
8816097 - 财政年份:2014
- 资助金额:
$ 31.97万 - 项目类别:
相似海外基金
Deciphering the role of adipose tissue in common metabolic disease via adipose tissue proteomics
通过脂肪组织蛋白质组学解读脂肪组织在常见代谢疾病中的作用
- 批准号:
MR/Y013891/1 - 财政年份:2024
- 资助金额:
$ 31.97万 - 项目类别:
Research Grant
ESTABLISHING THE ROLE OF ADIPOSE TISSUE INFLAMMATION IN THE REGULATION OF MUSCLE MASS IN OLDER PEOPLE
确定脂肪组织炎症在老年人肌肉质量调节中的作用
- 批准号:
BB/Y006542/1 - 财政年份:2024
- 资助金额:
$ 31.97万 - 项目类别:
Research Grant
Canadian Alliance of Healthy Hearts and Minds: Dissecting the Pathways Linking Ectopic Adipose Tissue to Cognitive Dysfunction
加拿大健康心灵联盟:剖析异位脂肪组织与认知功能障碍之间的联系途径
- 批准号:
479570 - 财政年份:2023
- 资助金额:
$ 31.97万 - 项目类别:
Operating Grants
Determinants of Longitudinal Progression of Adipose Tissue Inflammation in Individuals at High-Risk for Type 2 Diabetes: Novel Insights from Metabolomic Profiling
2 型糖尿病高危个体脂肪组织炎症纵向进展的决定因素:代谢组学分析的新见解
- 批准号:
488898 - 财政年份:2023
- 资助金额:
$ 31.97万 - 项目类别:
Operating Grants
Activation of human brown adipose tissue using food ingredients that enhance the bioavailability of nitric oxide
使用增强一氧化氮生物利用度的食品成分激活人体棕色脂肪组织
- 批准号:
23H03323 - 财政年份:2023
- 资助金额:
$ 31.97万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of new lung regeneration therapies by elucidating the lung regeneration mechanism of adipose tissue-derived stem cells
通过阐明脂肪组织干细胞的肺再生机制开发新的肺再生疗法
- 批准号:
23K08293 - 财政年份:2023
- 资助金额:
$ 31.97万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A study on the role of brown adipose tissue in the development and maintenance of skeletal muscles
棕色脂肪组织在骨骼肌发育和维持中作用的研究
- 批准号:
23K19922 - 财政年份:2023
- 资助金额:
$ 31.97万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Adipose Tissue T Cell Polarization and Metabolic Health in Persons Living with HIV
HIV 感染者的脂肪组织 T 细胞极化和代谢健康
- 批准号:
10619176 - 财政年份:2023
- 资助金额:
$ 31.97万 - 项目类别:
Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation
下丘脑腹内侧区的雌激素信号调节脂肪组织代谢适应
- 批准号:
10604611 - 财政年份:2023
- 资助金额:
$ 31.97万 - 项目类别:
Obesity and Childhood Asthma: The Role of Adipose Tissue
肥胖和儿童哮喘:脂肪组织的作用
- 批准号:
10813753 - 财政年份:2023
- 资助金额:
$ 31.97万 - 项目类别: