Role of bFGF low affinity receptors in childhood HIVAN

bFGF 低亲和力受体在儿童 HIVAN 中的作用

• 批准号: 10613597
• 负责人: PATRICIO E RAY
• 金额: $ 56.11万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613597
• 关键词: AIDS-Associated Nephropathy; APOL1 gene; Acceleration; Adolescent; Affect; Affinity; Africa South of the Sahara; African ancestry; Area; Binding; CRISPR/Cas technology; Cell Line; Cells; Child; Childhood; Chronic Kidney Failure; Circulation; Clinical; Cytoskeleton; District of Columbia; Endothelial Cells; Epidemiology; Epithelial Cells; FGF2 gene; Funding; Genes; Genetic Risk; Genotype; Glomerular Capillary; Grant; Growth Factor; HIV; HIV-1; Heparan Sulfate Proteoglycan; Heparin Binding; Human; Infection; Injury; Injury to Kidney; Kidney; Knowledge; Membrane; Modernization; Mus; Names; Outcome; Pathogenesis; Pathway interactions; Permeability; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Positioning Attribute; Precipitating Factors; Process; Proteins; Risk; Risk Factors; Role; Sampling; Signal Pathway; Structure; TNF gene; Technology; Testing; Transgenic Mice; Transgenic Organisms; Tubular formation; Urine; VEGFA gene; Viral Proteins; Viral reservoir; antiretroviral therapy; cytokine; fly; glomerular endothelium; high risk; kidney cell; mouse model; perinatal HIV; podocyte; programs; receptor; recruit; renal epithelium; rho; risk variant; synergism; transcriptome; urinary

PROJECT SUMMARY/ABSTRACT Most of the 2.5 million children and adolescents living with HIV-1 (CALWH) worldwide reside in Sub-Saharan Africa. Those who carry two copies of the APOL1 risk alleles (RA) are at higher risk of developing HIV-chronic kidney diseases (HIV-CKD) if they are not treated continuously with modern anti-retroviral therapy (ART) throughout childhood. During the last grant cycle, we followed the outcome of ~ 200 CALWH in the Washington DC area for an average period of 5 years, and found that many developed HIV-CKD despite ART. We also found that children with high plasma and urine levels of the heparin binding cytokine Fibroblast Growth Factor-2 (FGF- 2), were at further risk of developing HIV-CKD, and that FGF-2 increased the renal recruitment and attachment of HIV+ cells in mice. Thus, we hypothesize that FGF-2 release into the circulation accelerates the progression of childhood HIV-CKD, acting in synergy with the APOL1-RA and other HIV proteins, by facilitating the renal recruitment of HIV-infected cells, as well as the infection and/or injury of renal cells despite ART. We further hypothesize that FGF-2 precipitates the detachment of viable podocytes and tubular epithelial cells (REc), and that the phenotype and transcriptome profiles of these cells can be used to distinguish CALWH undergoing HIVAN and/or other progressive HIV-CKD, and to follow their outcome in a non-invasive manner. This hypothesis will be tested in three aims. In aim 1, we will define how FGF-2 and APOL1-RA interact to precipitate HIV-CKDs in CALWH on ART, and define the clinical value of single cell urinary transcriptome profiles to distinguish CALWH undergoing HIVAN and/or other progressive HIV-CKD. In aim 2, we will determine how FGF-2 and APOL1-RA interact to modulate the infection, injury, and/or survival of HIV-infected cells cultured from children with HIV- CKD. In aim 3, we will use two new mouse models of childhood HIV-CKD, to determine how FGF-2 interacts with APOL1-RA and HIV-Nef to precipitate the detachment of podocytes/REc and accelerate the progression of HIV-CKD. In addition, we will identify the most relevant signaling pathways involved in these processes, and define how drugs that block the selected pathways affect the progression of HIV-CKD in young mice.

项目总结/摘要 全世界250万感染艾滋病毒1型的儿童和青少年中，大多数居住在撒哈拉以南非洲， 非洲携带两个APOL 1风险等位基因（RA）的人患HIV慢性感染的风险更高。 肾脏疾病（HIV-CKD），如果他们没有持续接受现代抗逆转录病毒治疗（ART） 整个童年。在上一个赠款周期，我们跟踪了华盛顿约200个CALWH的结果 DC地区的平均时间为5年，并发现许多发展HIV-CKD，尽管ART。 血浆和尿液中肝素结合细胞因子成纤维细胞生长因子-2（FGF-2）水平高的儿童， 2），有进一步发展为HIV-CKD的风险，FGF-2增加了肾脏募集和附着， HIV+细胞的数量。因此，我们假设FGF-2释放到循环中加速了 与APOL 1-RA和其他HIV蛋白协同作用，通过促进肾脏 招募HIV感染的细胞，以及尽管ART肾细胞的感染和/或损伤。 假设FGF-2促进有活力的足细胞和肾小管上皮细胞（REC）的分离， 这些细胞的表型和转录组谱可用于区分CALWH的发生， HIVAN和/或其他进行性HIV-CKD，并以非侵入性方式随访其结果。这一假设 将在三个目标中进行测试。在目标1中，我们将定义FGF-2和APOL 1-RA如何相互作用以促进HIV-CKD CALWH对ART的影响，并确定单细胞尿转录组谱鉴别CALWH的临床价值 患有HIVAN和/或其他进行性HIV-CKD。在目标2中，我们将确定FGF-2和APOL 1-RA如何在细胞内表达。 相互作用以调节从HIV感染儿童培养的HIV感染细胞的感染、损伤和/或存活， CKD。在目标3中，我们将使用两种新的儿童HIV-CKD小鼠模型，以确定FGF-2如何相互作用 与APOL 1-RA和HIV-Nef一起沉淀足细胞/REC的脱离并加速 HIV-CKD。此外，我们将确定参与这些过程的最相关的信号通路， 确定阻断选定途径的药物如何影响幼龄小鼠中HIV-CKD的进展。

项目成果

A pilot study of urinary fibroblast growth factor-2 and epithelial growth factor as potential biomarkers of acute kidney injury in critically ill children.

• DOI: 10.1007/s00467-013-2543-3
• 发表时间: 2013-11
• 期刊: PEDIATRIC NEPHROLOGY
• 影响因子: 3
• 作者: Wai, Kitman;Soler-Garcia, Angel A.;Perazzo, Sofia;Mattison, Parnell;Ray, Patricio E.
• 通讯作者: Ray, Patricio E.

Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells.

人胎儿系膜细胞中血管紧张素 II 和碱性成纤维细胞生长因子有丝分裂途径。

• DOI: 10.1203/00006450-200005000-00010
• 发表时间: 2000
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Izevbigie,EB;Gutkind,JS;Ray,PE
• 通讯作者: Ray,PE

How complicated can it be? The link between APOL1 risk variants and lipoprotein heterogeneity in kidney and cardiovascular diseases.

它能有多复杂？

• DOI: 10.1093/ndt/gfv357
• 发表时间: 2016
• 期刊: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
• 作者: Hu,Chien-AnA;Ray,PatricioE
• 通讯作者: Ray,PatricioE

A novel urinary biomarker profile to identify acute kidney injury (AKI) in critically ill neonates: a pilot study.

• DOI: 10.1007/s00467-013-2524-6
• 发表时间: 2013-11
• 期刊: PEDIATRIC NEPHROLOGY
• 影响因子: 3
• 作者: Hoffman, Suma Bhat;Massaro, An N.;Soler-Garcia, Angel A.;Perazzo, Sofia;Ray, Patricio E.
• 通讯作者: Ray, Patricio E.

Regulation of HIV-1 transcription at 3% versus 21% oxygen concentration.

• DOI: 10.1002/jcp.21882
• 发表时间: 2009-11
• 期刊: JOURNAL OF CELLULAR PHYSIOLOGY
• 影响因子: 5.6
• 作者: Charles, Sharroya;Ammosova, Tatyana;Cardenas, Jessica;Foster, Altreisha;Rotimi, Jamie;Jerebtsova, Marina;Ayodeji, Abisola A.;Niu, Xiaomei;Ray, Patricio E.;Gordeuk, Victor R.;Kashanchi, Fatah;Nekhaii, Sergei
• 通讯作者: Nekhaii, Sergei