The Effect of Sodium (Na+) on Kidney B cells in Lupus Nephritis

钠 (Na ) 对狼疮性肾炎肾 B 细胞的影响

• 批准号: 10684098
• 负责人: Irene Chernova
• 金额: $ 16.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684098
• 关键词: Address; Affect; Animal Model; Animals; Antibodies; Antibody Formation; Antigen-Presenting Cells; Autoimmune; Autoimmune Diseases; Award; B-Lymphocytes; Bathing; Bioinformatics; Biopsy; Bone Marrow; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chimera organism; Data; Deposition; Development; Development Plans; Dissection; Diuretics; End stage renal failure; Energy Metabolism; Environment; Exhibits; Experimental Water Deprivation; Exposure to; Flow Cytometry; Fluorescent in Situ Hybridization; Generations; Genetic; Genetic Transcription; Geography; Goals; Grant; Human; Imaging Techniques; Immunobiology; Immunofluorescence Immunologic; Immunohistochemistry; Immunology; In Situ; Infiltration; Institution; Ions; Kidney; Kidney Diseases; Knock-out; Lupus; Lupus Nephritis; Lymphocyte; Lymphocytic Infiltrate; Manuscripts; Measures; Mediating; Mentorship; Morbidity - disease rate; Mus; Na(+)-K(+)-Exchanging ATPase; Nephritis; Nephrology; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Physicians; Population; Positioning Attribute; Preparation; Production; Proteinuria; RNA; Renal function; Research; Research Personnel; Scientist; Serum; Severity of illness; Shapes; Sodium; Stress; Systemic Lupus Erythematosus; T-Lymphocyte; TAC1 gene; Technology; Testing; Tissues; Universities; Water; Wild Type Mouse; Work; career; career development; cytokine; design; experimental study; high salt diet; in situ imaging; in vivo; interstitial; ionic balance; kidney biopsy; kidney cortex; kidney medulla; lupus prone mice; medical schools; mortality; novel; pharmacologic; programs; statistics; systemic autoimmune disease

Project Summary Lupus nephritis is the kidney manifestation of the autoimmune disease systemic lupus erythematosus (SLE, lupus); 10% of those afflicted progress to end stage kidney disease. Lupus nephritis kidneys are characterized by a profound lymphocytic infiltrate and the degree of infiltrate, including B lymphocytes specifically, correlates with tissue damage and disease severity. Kidneys are also characterized by axial concentration gradients of sodium (Na+), up to 2-fold higher than serum. Thus the inimical kidney environment presents unique survival challenges for infiltrating lymphocytes that may shape their phenotype and function. The function of intrarenal B cells and the pathways they employ to adapt to the hostile kidney environment remain uncharacterized. My preliminary data demonstrate that B cells from lupus-prone mice exhibit enhanced survival when exposed to high Na+ ex vivo as compared to wildtype mice. This effect was mediated by high expression of sodium potassium ATPase (Na+-K+-ATPase, NKA), a key regulator of cellular ionic balance. I have also shown that kidney-infiltrating B cells in murine lupus adapted to elevated [Na+] and that the expression of in vivo NKA correlated with the ability of infiltrating B cells to persist in the kidney. Pharmacological inhibition of NKA and genetic knockout of the NKA g subunit, the latter not previously known to be expressed in B cells, resulted in reduced kidney B cell infiltration and amelioration of proteinuria. B cells in renal biopsies of SLE patients also expressed more NKA than intrarenal T cells, suggesting the same NKA-regulated B cell survival pathway is operative in human SLE nephritis. How Na+ affects cell death pathways and whether it regulates B cell function, such as antibody or cytokine production, is unknown. I hypothesize that Na+ modulates intrarenal B cell death pathways and function, dissection of which will augment understanding of lupus nephritis pathogenesis. In Aim 1, I will investigate death pathways that lupus versus healthy control B cells undergo when exposed to high Na+ ex vivo. In Aim 2, I will assess B cell function upon alteration of kidney Na+ environment in mice while in Aim 3 I will utilize in situ imaging to define the functional landscape of these pathogenic cells in human SLE nephritis biopsies. Together these studies will help identify kidney-specific targets for the treatment of SLE nephritis. The candidate for this award is a physician-scientist with dual expertise in nephrology and immunology. Her long-term goals are to be an independent academic researcher with a focus on autoimmune kidney disease and lymphocyte-ion interactions. This award would allow the candidate to receive exceptional mentorship from the departments of Immunobiology and Nephrology at Yale University School of Medicine, a premier research institution. A comprehensive career development plan with coursework in bioinformatics and statistics, acquisition of RNA hybridization and imaging techniques and professional development focused on grant and manuscript preparation is designed to promote the candidate’s career goals and will be facilitated by this award.

项目摘要 狼疮肾炎是自身免疫性疾病全身性红斑狼疮的肾脏表现（SLE，SLE，SLE， 狼疮）;遭受痛苦的末期肾脏疾病的进展中，有10％。狼疮肾炎肾脏的特征 通过深刻的淋巴细胞浸润和浸润程度，包括B淋巴细胞，特别是相关的 具有组织损伤和疾病严重程度。肾脏也以轴向浓度梯度为特征 钠（Na+），比血清高2倍。那是毫无疑问的肾脏环境，呈现出独特的生存 浸润淋巴细胞可能影响其表型和功能的挑战。肾内B的功能 细胞及其适应敌对肾脏环境的途径仍然没有表征。 我的初步数据表明，暴露于狼疮的小鼠的B细胞暴露于暴露于 与野生型小鼠相比，高Na+ Ex ex Vivo。这种作用是由钠的高表达介导的 钾ATPase（Na+-K+-ATPase，NKA），这是细胞离子平衡的关键调节剂。我也表明 鼠狼疮中的肾脏浸入B细胞适应升高的[Na+]，并且体内NKA的表达 与浸润B细胞在肾脏中持续存在的能力相关。 NKA和 NKA G亚基的遗传敲除，后者以前未知在B细胞中表达，导致 肾脏B细胞浸润​​减少和蛋白尿的改善。 SLE患者肾脏活检中的B细胞也 与肾内T细胞相比，NKA表达更多，表明相同的NKA调节的B细胞存活途径是 人SLE肾炎手术。 Na+如何影响细胞死亡途径及其是否调节B细胞功能， 例如抗体或细胞因子产生，尚不清楚。我假设Na+调节了肾内B细胞死亡 途径和功能，解剖会增强对狼疮性肾炎发病机理的理解。目标 1，我将研究死亡途径，即暴露于高Na+时狼疮与健康对照B细胞发生 前体。在AIM 2中，我将在AIM 3中的小鼠肾脏Na+环境改变时评估B细胞功能 我将利用原位成像来定义人SLE肾炎中这些病原细胞的功能景观 活检。这些研究共同有助于确定肾脏特异性靶标的用于治疗SLE肾炎的靶标。 该奖项的候选人是肾脏和免疫学双重专家的身体科学家。她 长期目标是成为一名独立的学术研究员，专注于自身免疫性肾脏疾病和 淋巴细胞 - 离子相互作用。该奖项将使候选人可以从 耶鲁大学医学院免疫生物学和肾脏科学系，一项主要研究 机构。一项全面的职业发展计划，具有生物信息学和统计学的课程， RNA杂交和成像技术的获取以及专业发展的重点是赠款和 手稿准备旨在促进候选人的职业目标，并将由该奖项准备。