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
• 负责人: Douglas Brock Cines
• 金额: $ 58万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133060
• 关键词: Address; Adult; Affect; Anti-Bacterial Agents; Antibiotic Prophylaxis; Antibiotics; Automobile Driving; Back; Biological; Biological Assay; Bone Marrow Transplantation; Cell physiology; Child; Chronic Kidney Failure; Copy Number Polymorphism; DNA; DNA copy number; Data; Defensins; Disease; Duct (organ) structure; Ductal Epithelial Cell; End stage renal failure; Epithelial Cells; Exposure to; Gene Dosage; Genes; Genetic; Health; Host Defense; Human; Hypertension; Image; Immune; Immune system; In Vitro; Individual; Infection; Integration Host Factors; Intercalated Cell; Intercalated Duct; Invaded; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Lead; Leukocytes; Messenger RNA; Microbe; Molecular; Mus; Organ; Pathology; Patient Care; Patients; Play; Predisposition; Process; Production; Prophylactic treatment; Proteins; Proteomics; Publications; Pyelonephritis; Radiation; Recurrence; Reflux; Regulation; Reporting; Research; Risk; Role; Secondary to; Source; Techniques; Transplantation; Tubular formation; Urinary tract; Urinary tract infection; Urine; Uropathogen; Variant; Vesico-Ureteral Reflux; alpha-Defensins; antimicrobial; antimicrobial peptide; base; bench to bedside; clinically relevant; experience; gene product; human neutrophil peptide 1; humanized mouse; improved; infection risk; insight; kidney infection; mouse model; neutrophil; new therapeutic target; pathogen; personalized medicine; prevent; renal scarring; response; risk stratification; synergism; targeted treatment

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.

项目概要/摘要 膀胱输尿管反流影响 1-2% 的儿童，其中多达三分之一的患者会出现尿路问题 肾脏，特别是集合管在肾脏的先天防御和感染（UTI）中发挥着关键作用。 我们的研究小组已经证明，闰细胞是多种先天性细胞的主要来源。 免疫抗菌肽 DEFA1A3（α-防御素 1-3）及其抗菌蛋白（AMP）产品，人类。 中性粒细胞蛋白 1-3 (HNP1-3) 在人类肾脏的先天免疫防御中非常重要，就在今年。 报道 a) DEFA1A3 DNA 拷贝数的变化与 UTI 敏感性和抗生素相关 膀胱输尿管反流和尿路感染儿童的反应，b) DEFA1A3 mRNA 和蛋白产物，HNP1-3 表达为 不限于白细胞，还存在于肾集合管上皮细胞中，并且 c) 尿 HNP1-3 在 我们的研究结果与 HNP1-3 作为快速破坏性 AMP 的已知功能相关。 这些发现很重要，因为目前无法对 VUR 和 UTI 进行管理。 根据个体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。 肾盂肾炎风险，儿童将暴露于不必要的成像相关辐射和抗生素预防 如果所有患者都接受保守治疗，则有一部分患者可能会出现可预防的肾病。 此外，在集合肾管细胞中表达的 DEFA1A3 的鉴定增加了疤痕形成和慢性肾脏疾病。 由于 DEFA1A3 DNA 拷贝数，DEFA1A3 表达可能成为治疗的靶点。 变异与 UTI 相关，最近发现肾集合管细胞表达 HNP1-3，决定了 HNP1-3 在肾脏中的作用代表了临床相关的研究方向。 研究中，我们发现肾源性和中性粒细胞源性 DEFA1A3/HNP1-3 在细胞生理学/ 病理学并受 DNA 拷贝数变异的影响。 为此，我们将确定对肾储存、分泌和激活至关重要的独特分子机制。 人类和小鼠尿路感染中衍生的α防御素（目标1）我们将利用小鼠模型利用蛋白质组学技术。 在目标 2 中，我们将使用小鼠肾脏模型。 移植α-防御素人源化小鼠，以检查肾脏在先天防御中的作用 在目标 3 中，我们将利用该小鼠模型和体外研究来剖析 DNA 拷贝数的作用。 DEFA1A3 位点在 UTI 敏感性和抗生素协同作用中的变化。

项目成果

Aptamer based proteomic pilot study reveals a urine signature indicative of pediatric urinary tract infections.

基于适体的蛋白质组初步研究揭示了表明儿童尿路感染的尿液特征。

• 发表时间: 2020
• 影响因子: 3.7
• 作者: Dong, Liang;Watson, Joshua;Cao, Sha;Arregui, Samuel;Saxena, Vijay;Ketz, John;Awol, Abduselam K;Cohen, Daniel M;Caterino, Jeffrey M;Hains, David S;Schwaderer, Andrew L
• 通讯作者: Schwaderer, Andrew L

Intercalated cell function, kidney innate immunity, and urinary tract infections.

闰细胞功能、肾脏先天免疫和尿路感染。

• 发表时间: 2024-01-16
• 作者: Schwaderer, Andrew L;Rajadhyaksha, Evan;Canas, Jorge;Saxena, Vijay;Hains, David S
• 通讯作者: Hains, David S

DEFA1A3 DNA gene-dosage regulates the kidney innate immune response during upper urinary tract infection.

DEFA1A3 DNA 基因剂量调节上尿路感染期间肾脏的先天免疫反应。

• 发表时间: 2024-06
• 影响因子: 4.4
• 作者: Canas, Jorge J;Arregui, Samuel W;Zhang, Shaobo;Knox, Taylor;Calvert, Christi;Saxena, Vijay;Schwaderer, Andrew L;Hains, David S
• 通讯作者: Hains, David S