Role of VEGF in Glomerular Endothelial Health & Diseases

VEGF 在肾小球内皮健康中的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): Glomerular endothelial damage plays an important role in the pathogenesis of several proteinuric renal disorders such as preeclampsia (PE), thrombotic microangiopathic purpuras (TTP), renal transplant rejection and various endocapillary glomerulonephritides. However, the mechanisms of endothelial damage and proteinuria in these disorders are poorly understood. It has been shown that vascular endothelial growth factor (VEGF) is not only an essential molecule for glomerulogenesis and kidney development, but also important for glomerular capillary repair in experimental models of glomerular disorders such as glomerulonephritides and TTP. VEGF is also abundantly expressed in the adult glomerulus during nondiseased states, but its role in glomerular health and disease is unclear. Recently, we have demonstrated that excess placental production of sFIt-1 (a circulating VEGF antagonist) in patients with PE is responsible for proteinuria, hypertension and. qlomerular endotheliosis, the classic pathologic lesion of PE. Moreover, massive proteinuria with glomerular endotheliosis has been recently described in glomerular podocyte-specific VEGF knockout mice. Additionally, VEGF signaling inhibitors usage in clinical cancer trials have resulted in proteinuria and hypertension in humans. Therefore, we hypothesize that VEGF and its receptors play an important role in not only maintaining glomerular endothelial health but also in maintaining normal glomerular integrity and the barrier to proteinuria. Disruption of VEGF signaling by antagonists may result in proteinuria in the short term and glomerulosclerosis in the long term. In this proposal, we will first characterize our sFIt-1 induced model of proteinuria and endotheliosis to understand the mechanisms of proteinuria in VEGF-deficient states. We will then elucidate the VEGF signaling pathways that mediate the barrier against proteinuria and maintain endothelial health using chimeric VEGF receptors in glomerular endothelial cell culture studies in vitro to be followed by definitive in vivo studies in rats using VEGF receptor agonists (such as placental growth factor that activates only Fit-1 and not FIk-l) and neutralizing antibodies against various VEGF receptors. We will then study the long-term renal and vascular consequences of VEGF blockade in rats specifically seeking the development of glomerulosclerosis and hypertension. Finally, we will study the effects of VEGF inhibitors and VEGF agonists in anti-Thyl.1 nephritis, a well-characterized experimental model of glomerulonephritis, in which capillary repair is thought to be important for the resolution of nephritis. Together, these studies will facilitate us to achieve our goal of understanding the role of VEGF and glomerular endothelial cell dysfunction in the pathogenesis of proteinuria and may lead to novel therapeutic options for glomerular endothelial diseases as well as clarify the renal toxicity profile of VEGF signaling inhibitors being developed for other diseases such as cancer.
描述(由申请人提供):肾小球内皮损伤在几种蛋白尿性肾脏疾病的发病机制中起重要作用,如先兆子痫(PE)、血栓性微血管病性紫癜(TTP)、肾移植排斥反应和各种毛细血管内肾小球肾炎。 然而,这些疾病中内皮损伤和蛋白尿的机制知之甚少。 血管内皮生长因子(vascular endothelial growth factor,VEGF)不仅是肾小球形成和肾脏发育的必需分子,而且在肾小球疾病如肾小球肾炎和TTP的实验模型中对肾小球毛细血管修复也很重要。 VEGF在非疾病状态下也在成人肾小球中大量表达,但其在肾小球健康和疾病中的作用尚不清楚。 最近,我们已经证明,胎盘分泌过量的sFIt-1(一种循环中的VEGF拮抗剂)是导致PE患者蛋白尿、高血压和高血压的原因。肾小球内皮增生,PE的典型病理损害。 此外,大量的蛋白尿与肾小球内皮细胞增生最近已被描述在肾小球足细胞特异性VEGF基因敲除小鼠。 此外,VEGF信号传导抑制剂在临床癌症试验中的使用导致人类蛋白尿和高血压。因此,我们推测VEGF及其受体不仅在维持肾小球内皮健康方面,而且在维持正常肾小球完整性和蛋白尿屏障方面发挥重要作用。拮抗剂对VEGF信号传导的破坏可能在短期内导致蛋白尿,在长期内导致肾小球硬化。在这个提议中,我们将首先描述我们的sFIt-1诱导的蛋白尿和内皮增生模型,以了解VEGF缺乏状态下蛋白尿的机制。然后,我们将在体外肾小球内皮细胞培养研究中使用嵌合VEGF受体阐明介导针对蛋白尿的屏障并维持内皮健康的VEGF信号传导途径,随后在大鼠中使用VEGF受体激动剂(如仅激活Flt-I而不激活FIk-I的胎盘生长因子)和针对各种VEGF受体的中和抗体进行确定性体内研究。 然后,我们将研究VEGF阻断大鼠肾脏和血管的长期后果,特别是寻求肾小球硬化和高血压的发展。 最后,我们将研究VEGF抑制剂和VEGF激动剂在抗Thyl.1肾炎中的作用,抗Thyl.1肾炎是肾小球肾炎的良好表征的实验模型,其中毛细血管修复被认为对于肾炎的消退是重要的。总之,这些研究将有助于我们实现理解VEGF和肾小球内皮细胞功能障碍在蛋白尿发病机制中的作用的目标,并可能为肾小球内皮疾病提供新的治疗选择,并阐明正在开发的用于其他疾病(如癌症)的VEGF信号传导抑制剂的肾毒性特征。

项目成果

期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Angiogenic factors in the pathogenesis of preeclampsia.
先兆子痫发病机制中的血管生成因素。
  • DOI:
    10.1016/s0070-2153(05)71009-7
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yuan,Hai-Tao;Haig,David;AnanthKarumanchi,S
  • 通讯作者:
    AnanthKarumanchi,S
Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?
{{ 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 }}

S. Ananth Karumanchi其他文献

ニコチンアミドは妊娠高血圧に有効である
烟酰胺对妊娠高血压有效
  • DOI:
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0
  • 作者:
    高橋信行;Feng Li;Charles Jennette;S. Ananth Karumanchi;Oliver Smithies;高橋信行;高橋信行
  • 通讯作者:
    高橋信行
993 Plasma sFlt-1/PlGF ratio in mom and severe adverse neonatal outcomes in non-preeclamptic patients
  • DOI:
    10.1016/j.ajog.2023.11.1020
  • 发表时间:
    2024-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jimmy Espinoza;Vinicius Calsavara;Elizabeth Lemoine;Sarah Kilpatrick;Ravi Thadhani;S. Ananth Karumanchi
  • 通讯作者:
    S. Ananth Karumanchi
ニコチンアミドは妊娠高血圧腎症に有効である
烟酰胺对先兆子痫有效
  • DOI:
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0
  • 作者:
    高橋信行;Feng Li;Charles Jennette;Oliver Smithies;S. Ananth Karumanchi
  • 通讯作者:
    S. Ananth Karumanchi
1059 Maternal Angiogenic Imbalance & Placental Sexual Dimorphism
  • DOI:
    10.1016/j.ajog.2023.11.1086
  • 发表时间:
    2024-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Elizabeth Lemoine;Vinicius Calsavara;Ravi Thadhani;Sarah Kilpatrick;S. Ananth Karumanchi;Kim Boggess
  • 通讯作者:
    Kim Boggess
Lipid-delivery system could treat life-threatening pregnancy complication
脂质递送系统可治疗危及生命的妊娠并发症
  • DOI:
    10.1038/d41586-024-03853-w
  • 发表时间:
    2024-12-11
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Ravi Thadhani;S. Ananth Karumanchi
  • 通讯作者:
    S. Ananth Karumanchi

S. Ananth Karumanchi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('S. Ananth Karumanchi', 18)}}的其他基金

Placental Organoids for Modeling and Treating Preeclampsia
用于建模和治疗先兆子痫的胎盘类器官
  • 批准号:
    10464766
  • 财政年份:
    2022
  • 资助金额:
    $ 33.33万
  • 项目类别:
Placental Organoids to Model Preeclampsia
胎盘类器官模拟先兆子痫
  • 批准号:
    10594844
  • 财政年份:
    2022
  • 资助金额:
    $ 33.33万
  • 项目类别:
Role of ADAMTS13 in Maternal Complications of Preeclampsia
ADAMTS13 在先兆子痫孕产妇并发症中的作用
  • 批准号:
    9119325
  • 财政年份:
    2016
  • 资助金额:
    $ 33.33万
  • 项目类别:
2012 Endothelial Cell Phenotypes in Health & Disease GRC/GRS
2012 健康中的内皮细胞表型
  • 批准号:
    8390350
  • 财政年份:
    2012
  • 资助金额:
    $ 33.33万
  • 项目类别:
Redefining Vitamin D Deficiency: The Role of Bioavailable Vitamin D
重新定义维生素 D 缺乏症:生物可利用维生素 D 的作用
  • 批准号:
    9015435
  • 财政年份:
    2012
  • 资助金额:
    $ 33.33万
  • 项目类别:
Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
  • 批准号:
    7010387
  • 财政年份:
    2005
  • 资助金额:
    $ 33.33万
  • 项目类别:
Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
  • 批准号:
    7365256
  • 财政年份:
    2005
  • 资助金额:
    $ 33.33万
  • 项目类别:
Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
  • 批准号:
    7174642
  • 财政年份:
    2005
  • 资助金额:
    $ 33.33万
  • 项目类别:
Angiogenesis-related gene products in preeclampsia
先兆子痫中血管生成相关的基因产物
  • 批准号:
    6870361
  • 财政年份:
    2005
  • 资助金额:
    $ 33.33万
  • 项目类别:
Role of VEGF in Glomerular Endothelial Health & Diseases
VEGF 在肾小球内皮健康中的作用
  • 批准号:
    6822487
  • 财政年份:
    2004
  • 资助金额:
    $ 33.33万
  • 项目类别:

相似国自然基金

Agonist-GPR119-Gs复合物的结构生物学研究
  • 批准号:
    32000851
  • 批准年份:
    2020
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
  • 批准号:
    24K12256
  • 财政年份:
    2024
  • 资助金额:
    $ 33.33万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
  • 批准号:
    24K19176
  • 财政年份:
    2024
  • 资助金额:
    $ 33.33万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
  • 批准号:
    10578068
  • 财政年份:
    2023
  • 资助金额:
    $ 33.33万
  • 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
  • 批准号:
    10933287
  • 财政年份:
    2023
  • 资助金额:
    $ 33.33万
  • 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
  • 批准号:
    10650593
  • 财政年份:
    2023
  • 资助金额:
    $ 33.33万
  • 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
  • 批准号:
    10649275
  • 财政年份:
    2023
  • 资助金额:
    $ 33.33万
  • 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
  • 批准号:
    10784209
  • 财政年份:
    2023
  • 资助金额:
    $ 33.33万
  • 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
  • 批准号:
    10734158
  • 财政年份:
    2023
  • 资助金额:
    $ 33.33万
  • 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
  • 批准号:
    10580259
  • 财政年份:
    2023
  • 资助金额:
    $ 33.33万
  • 项目类别:
Identification and characterization of a plant growth promoter from wild plants: is this a novel plant hormone agonist?
野生植物中植物生长促进剂的鉴定和表征:这是一种新型植物激素激动剂吗?
  • 批准号:
    23K05057
  • 财政年份:
    2023
  • 资助金额:
    $ 33.33万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了