Genetic Regulation, Tubular Processing and Clinical Relevance of Collecting Duct alpha-Defensins 1-3
集合管 α-防御素 1-3 的遗传调控、管状加工和临床相关性
基本信息
- 批准号:9906213
- 负责人:
- 金额:$ 58.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAnti-Bacterial AgentsAntibiotic ProphylaxisAntibioticsAutomobile DrivingBackBiologicalBiological AssayBone Marrow TransplantationCell physiologyChildChronic Kidney FailureCopy Number PolymorphismDNADNA copy numberDataDefensinsDiseaseDuct (organ) structureDuctal Epithelial CellEnd stage renal failureEpithelial CellsExposure toGene DosageGenesGeneticHealthHost DefenseHumanHypertensionImageImmuneImmune systemIn VitroIndividualInfectionIntegration Host FactorsIntercalated CellIntercalated DuctInvadedKidneyKidney DiseasesKidney TransplantationKnowledgeLeadLeukocytesMessenger RNAMicrobeMolecularMusOrganPathologyPatient CarePatientsPlayPredispositionProcessProductionProphylactic treatmentProteinsProteomicsPublicationsPyelonephritisRadiationRecurrenceRefluxRegulationReportingResearchRiskRisk stratificationRoleSecondary toSourceTechniquesTransplantationTubular formationUrinary tractUrinary tract infectionUrineUropathogenVariantVesico-Ureteral Refluxalpha-Defensinsantimicrobialantimicrobial peptidebasebench to bedsideclinically relevantexperiencegene producthuman neutrophil peptide 1humanized mouseimprovedinfection riskinsightkidney infectionmouse modelneutrophilnew therapeutic targetpathogenpersonalized medicinepreventrenal scarringresponsesynergismtargeted treatment
项目摘要
PROJECT SUMMARY/ABSTRACT
Vesicoureteral reflux affects 1-2% of all children and up to one third of these patients will experience urinary tract
infections (UTI). The kidney and specifically the collect duct play a critical role in the innate defense of the kidney and
urinary tract. Our group has demonstrated that intercalated cells are the primary source of a wide spectrum of innate
immune antimicrobial peptides. DEFA1A3 (α-defensin 1-3) and its antimicrobial protein (AMP) product, human
neutrophil protein 1-3 (HNP1-3), is important in the innate immune defense of the human kidney. Just this year we have
reported that a) variations in the number of DEFA1A3 DNA copies correlate with UTI susceptibility and antibiotic
response in children with vesicoureteral reflux and UTIs, b) DEFA1A3 mRNA and protein product, HNP1-3 expression is
not limited to leukocytes, but also present in renal collecting duct epithelial cells and c) urine HNP1-3 increase during
UTIs. Our aforementioned findings correlate with the known function of HNP1-3 as an AMP that rapidly destroys
microbes. These finding are important because management of VUR and UTIs is complicated by the current inability to
personalize treatment according to individual risk. For instance if all patients are treated under the assumption of recurrent
pyelonephritis risk, children will be exposed to unnecessary imaging related radiation and antibiotic prophylaxis to
prevent UTIs. Conversely if all patients are treated conservatively, a subset will develop potentially preventable renal
scarring and chronic kidney disease. Further, identification of DEFA1A3 expressed in renal collecting duct cells, raises
the possibility that renal DEFA1A3 expression could be targeted for therapeutics. Because DEFA1A3 DNA copy number
variation is associated with UTI and the recent discovery that renal collecting duct cells express HNP1-3, determining
HNP1-3’s role in the kidney represents clinically relevant research direction. Based on prior publications and preliminary
studies, we hypothesize that renal- and neutrophil-derived DEFA1A3/HNP1-3 have distinct roles in cellular physiology/
pathology and are affected by DNA copy number variations.
To this end, we will identify the unique molecular mechanisms critical to storage, secretion and activation of renally-
derived alpha defensins in humans and murine UTI (Aim 1). We will utilize proteomic techniques using a mouse model
of bone marrow transplantation and urine in children with UTI. In Aim 2, we will use a murine model of kidney
transplantation of a humanized mouse for alpha-defensins to examine the kidney’s role in innate defense against
uropathogens. In Aim 3, we will utilize this murine model and in vitro studies to dissect the role of DNA copy number
variations in the DEFA1A3 locus in UTI susceptibility and antibiotic synergy.
项目总结/摘要
膀胱输尿管反流影响1-2%的儿童,其中三分之一的患者会出现尿路感染。
感染(UTI)。肾脏,特别是集合管在肾脏的先天防御中起着关键作用,
泌尿系统我们的研究小组已经证明,闰细胞是广泛的先天性免疫缺陷的主要来源。
免疫抗菌肽DEFA 1A 3(α-防御素1-3)及其抗菌蛋白(AMP)产物,人
中性粒细胞蛋白1-3(HNP 1 -3)在人肾脏的先天免疫防御中是重要的。就在今年,
报道a)DEFA 1A 3 DNA拷贝数的变化与UTI易感性和抗生素相关,
B)DEFA 1A 3 mRNA和蛋白产物、HNP 1 -3表达与膀胱输尿管反流和UTI儿童的反应有关。
不限于白细胞,而且还存在于肾集合管上皮细胞中,和c)在治疗期间尿HNP 1 -3增加,
尿路感染我们的上述发现与HNP 1 -3作为AMP的已知功能相关,
微生物这些发现是重要的,因为VUR和UTI的管理是复杂的,目前无法
根据个人风险进行个性化治疗。例如,如果所有患者都在复发的假设下接受治疗,
肾盂肾炎的风险,儿童将暴露于不必要的成像相关的辐射和抗生素预防,
预防UTI。相反,如果所有患者均接受保守治疗,则一个子集将发生潜在可预防的肾功能衰竭。
疤痕和慢性肾病。此外,鉴定在肾集合管细胞中表达的DEFA 1A 3,
肾DEFA 1A 3表达可能成为治疗靶点。因为DEFA 1A 3 DNA拷贝数
这种变异与UTI有关,最近发现肾集合管细胞表达HNP 1 -3,
HNP 1 -3在肾脏中的作用代表了临床相关的研究方向。根据以前的出版物和初步
研究中,我们假设肾脏和嗜中性粒细胞来源的DEFA 1A 3/HNP 1 -3在细胞生理学中具有不同的作用。
病理学和DNA拷贝数的变化影响。
为此,我们将确定对肾脏储存、分泌和激活至关重要的独特分子机制-
在人类和鼠UTI中衍生的α防御素(Aim 1)。我们将利用蛋白质组学技术,
骨髓移植和尿中的泌尿道感染的儿童。在目标2中,我们将使用小鼠肾脏模型,
移植α-防御素的人源化小鼠,以检查肾脏在先天防御中的作用,
泌尿病原体在目标3中,我们将利用这种小鼠模型和体外研究来剖析DNA拷贝数的作用。
UTI易感性和抗生素协同作用中DEFA 1A 3基因座的变异。
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)
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Douglas Brock Cines其他文献
Douglas Brock Cines的其他文献
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{{ truncateString('Douglas Brock Cines', 18)}}的其他基金
Structure-based Design of Rational PF4 Inhibitors in HIT
HIT 中合理 PF4 抑制剂的基于结构的设计
- 批准号:
9900853 - 财政年份:2018
- 资助金额:
$ 58.68万 - 项目类别:
Genetic Regulation, Tubular Processing and Clinical Relevance of Collecting Duct alpha-Defensins 1-3
集合管 α-防御素 1-3 的遗传调控、管状加工和临床相关性
- 批准号:
10133060 - 财政年份:2018
- 资助金额:
$ 58.68万 - 项目类别:
Prevention and management of perioperative pulmonary embolism
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8421570 - 财政年份:2013
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Prevention and management of perioperative pulmonary embolism
围手术期肺栓塞的预防和处理
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8723275 - 财政年份:2013
- 资助金额:
$ 58.68万 - 项目类别:
Nuclear translocation of urokinase/nucleolin complexes
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- 批准号:
7319578 - 财政年份:2007
- 资助金额:
$ 58.68万 - 项目类别:
Nuclear translocation of urokinase/nucleolin complexes
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- 资助金额:
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