Intracellular functions of APOL1 in the kidney
APOL1 在肾脏中的细胞内功能
基本信息
- 批准号:10383979
- 负责人:
- 金额:$ 56.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-23 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AIDS-Associated NephropathyAdvanced DevelopmentAdvocateAfrican AmericanAllelesApolipoproteinsAttenuatedBacterial Artificial ChromosomesBiochemicalBiochemical PathwayBiological ModelsBiological ProcessCell AdhesionCell LineCell SurvivalCellsChronic Kidney FailureClinicalClustered Regularly Interspaced Short Palindromic RepeatsDataDevelopmentDiseaseDisease modelEndosomesEnvironmentEventExposure toFocal Segmental GlomerulosclerosisFunctional disorderFutureGene ExpressionGene Expression ProfilingGenesGeneticGenetic PolymorphismGenetic Predisposition to DiseaseGenetic RiskGenetic TranscriptionGenotypeGoalsHIVHIV InfectionsHumanHypertensionIRF3 geneImmuneImmune responseImmune signalingIn VitroIndividualInheritance PatternsInheritedInjectionsInjuryInterferonsInvestigationKidneyKidney DiseasesKnock-outLinkLupus NephritisMediatingMethodsModelingMusOutcome StudyPathogenesisPathogenicityPathologyPattern recognition receptorPhenotypePoly I-CPrevalencePrevention strategyProcessReceptor ActivationRenal functionRiskRoleSignal TransductionStimulusStressTLR3 geneTestingTimeToll-like receptorsTransgenic MiceUnited StatesVariantVesicleVirusVirus DiseasesWorkadaptive immune responsebiological adaptation to stresscytotoxicitydensitydisease stressordisorder riskenvironmental stressorgain of functiongene environment interactiongenetic varianthigh riskimmune activationin vivoin vivo Modelinduced pluripotent stem cellinnate immune pathwayskidney biopsyloss of functionmouse modelnon-diabeticnovelnovel therapeuticspodocyteprotective effectracial health disparityrecessive genetic traitresponserisk variantstressortargeted treatmenttherapy designtraffickingtraittreatment strategy
项目摘要
ABSTRACT
Chronic kidney disease (CKD) in African Americans is one of the largest racial health disparities in the United
States. The cause for the increased risk has been attributed to recessive inheritance of allelic variants in the
gene for apolipoprotein L1 (APOL1). These APOL1 variants, known as G1 and G2, do not cause CKD on their
own, but CKD is caused by a combination of the inherited genetic risk plus exposure to a triggering environmental
stressor (a gene-environment interaction). Despite the association of CKD risk with APOL1 variants more than
ten years ago, the biological function of APOL1 in the kidney and the mechanism of pathogenesis in the setting
of a disease stressor remain unclear. Our long-term goal is to understand the genetics and biochemical
mechanism of CKD in African Americans caused by these APOL1 polymorphisms. To accomplish this goal, we
are studying HIV-associated nephropathy (HIVAN), the CKD most strongly associated APOL1 variants, and the
only CKD where the environmental stressor is known (HIV infection). HIVAN is an ideal disease model to dissect
biochemical pathways and cellular events intersected by APOL1 function, viral infection, and CKD. Our recent
studies have demonstrated, for the first time, a function for the common APOL1 allele, known as G0, in providing
protection against podocyte losses in HIVAN. Since APOL1 risk is a recessively inherited trait, this suggests
CKD may be caused, in part, by a loss-of-function process (i.e. absence of G0). In new preliminary data, G0
appears to associate with Toll-like receptors (TLRs) in intracellular vesicles containing HIV and facilitate signaling
events initiated by interferon regulatory factor (IRF)-3, and these processes were absent with the APOL1 risk
variants. Methods will use established in vitro HIV infection of human podocyte cell lines, in vivo models of HIVAN
and BAC-APOL1 transgenic mice that replicate endogenous human APOL1 expression. Aims will examine both
initial response to HIV infection in podocytes, and long-term in vivo studies of intercrosses between the HIVAN
and BAC-APOL1 transgenic mice evaluating effects on renal function and pathology. These studies also will
establish temporal and magnitude of stressor-induced APOL1 expression, the mechanism of the altered innate
immune activation through TLRs to IRF-3/7 signaling, and effect on podocyte phenotype (survival and cell
adhesion). The dominance of the G0 protective effect over the risk variant dysfunction will be tested in podocytes
and mouse models co-expressing G0 and the risk variants. These studies should advance our understanding of
gain- versus loss-of-function mechanism associated with the recessive inheritance of APOL1 risk alleles, and
the necessity of induced APOL1 expression to drive stress responses. Determining the contribution of G0
function versus risk variant dysfunction will have important clinical impact on further therapy design, as it will
establish whether replacement of G0 or suppression of the risk variants would be the more effective strategy.
摘要
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 }}
Leslie A Bruggeman其他文献
Leslie A Bruggeman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('Leslie A Bruggeman', 18)}}的其他基金
Mechanisms of Kidney Diseases Associated With APOL1 Variation
APOL1 变异相关肾脏疾病的机制
- 批准号:
10607630 - 财政年份:2023
- 资助金额:
$ 56.49万 - 项目类别:
Intracellular functions of APOL1 in the kidney
APOL1 在肾脏中的细胞内功能
- 批准号:
10493392 - 财政年份:2021
- 资助金额:
$ 56.49万 - 项目类别:
Intracellular functions of APOL1 in the kidney
APOL1 在肾脏中的细胞内功能
- 批准号:
10666584 - 财政年份:2021
- 资助金额:
$ 56.49万 - 项目类别:
Intracellular functions of APOL1 in the kidney
APOL1 在肾脏中的细胞内功能
- 批准号:
10252083 - 财政年份:2020
- 资助金额:
$ 56.49万 - 项目类别:
Kidney disease mechanisms associated with human genetic variation
与人类遗传变异相关的肾脏疾病机制
- 批准号:
9284462 - 财政年份:2014
- 资助金额:
$ 56.49万 - 项目类别:
Kidney disease mechanisms associated with human genetic variation
与人类遗传变异相关的肾脏疾病机制
- 批准号:
8642932 - 财政年份:2014
- 资助金额:
$ 56.49万 - 项目类别:
Kidney disease mechanisms associated with human genetic variation
与人类遗传变异相关的肾脏疾病机制
- 批准号:
9653298 - 财政年份:2014
- 资助金额:
$ 56.49万 - 项目类别:
Cell junction proteins in podocyte injury repair
足细胞损伤修复中的细胞连接蛋白
- 批准号:
8342329 - 财政年份:2012
- 资助金额:
$ 56.49万 - 项目类别:
相似海外基金
ADVANCED DEVELOPMENT OF LQ A LIPOSOME-BASED SAPONIN-CONTAINING ADJUVANT FOR USE IN PANSARBECOVIRUS VACCINES
用于 Pansarbecovirus 疫苗的 LQ A 脂质体含皂苷佐剂的先进开发
- 批准号:
10935820 - 财政年份:2023
- 资助金额:
$ 56.49万 - 项目类别:
ADVANCED DEVELOPMENT OF BBT-059 AS A RADIATION MEDICAL COUNTERMEASURE FOR DOSING UP TO 48H POST EXPOSURE"
BBT-059 的先进开发,作为辐射医学对策,可在暴露后 48 小时内进行给药”
- 批准号:
10932514 - 财政年份:2023
- 资助金额:
$ 56.49万 - 项目类别:
Advanced Development of a Combined Shigella-ETEC Vaccine
志贺氏菌-ETEC 联合疫苗的先进开发
- 批准号:
10704845 - 财政年份:2023
- 资助金额:
$ 56.49万 - 项目类别:
Advanced development of composite gene delivery and CAR engineering systems
复合基因递送和CAR工程系统的先进开发
- 批准号:
10709085 - 财政年份:2023
- 资助金额:
$ 56.49万 - 项目类别:
Advanced development and validation of an in vitro platform to phenotype brain metastatic tumor cells using artificial intelligence
使用人工智能对脑转移肿瘤细胞进行表型分析的体外平台的高级开发和验证
- 批准号:
10409385 - 财政年份:2022
- 资助金额:
$ 56.49万 - 项目类别:
ADVANCED DEVELOPMENT OF A VACCINE FOR PANDEMIC AND PRE-EMERGENT CORONAVIRUSES
针对大流行和突发冠状病毒的疫苗的高级开发
- 批准号:
10710595 - 财政年份:2022
- 资助金额:
$ 56.49万 - 项目类别:
Advanced development and validation of an in vitro platform to phenotype brain metastatic tumor cells using artificial intelligence
使用人工智能对脑转移肿瘤细胞进行表型分析的体外平台的高级开发和验证
- 批准号:
10630975 - 财政年份:2022
- 资助金额:
$ 56.49万 - 项目类别:
ADVANCED DEVELOPMENT OF A VACCINE CANDIDATE FOR STAPHYLOCOCCUS AUREUS INFECTION
金黄色葡萄球菌感染候选疫苗的高级开发
- 批准号:
10710588 - 财政年份:2022
- 资助金额:
$ 56.49万 - 项目类别:
ADVANCED DEVELOPMENT OF A VACCINE FOR PANDEMIC AND PRE-EMERGENT CORONAVIRUSES
针对大流行和突发冠状病毒的疫苗的高级开发
- 批准号:
10788051 - 财政年份:2022
- 资助金额:
$ 56.49万 - 项目类别:














{{item.name}}会员




