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: 10506196
• 负责人: Irene Chernova
• 金额: $ 16.76万
• 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/10506196
• 关键词: Address; Affect; Animal Model; Animals; Antibodies; Antibody Formation; Antigen-Presenting Cells; Autoimmune; Autoimmune Diseases; Award; B-Lymphocytes; Bioinformatics; Biopsy; Bone Marrow; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chimera organism; Data; Deposition; Development; Development Plans; Disease; 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; K ATPase; 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; Pharmacology; 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; 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.

项目概要 狼疮性肾炎是自身免疫性疾病系统性红斑狼疮（SLE， 狼疮）; 10% 的患者进展为终末期肾病。狼疮性肾炎肾脏的特点 通过深度淋巴细胞浸润和浸润程度（特别是 B 淋巴细胞）相关 与组织损伤和疾病严重程度有关。肾脏的特征还在于轴向浓度梯度 钠 (Na+)，比血清高 2 倍。因此，不利的肾脏环境提供了独特的生存能力 浸润淋巴细胞面临的挑战可能会影响其表型和功能。肾内B的功能 细胞及其适应不利的肾脏环境所采用的途径仍然未知。 我的初步数据表明，患有狼疮的小鼠的 B 细胞在暴露于 与野生型小鼠相比，体外 Na+ 含量较高。这种效应是由钠的高表达介导的 钾 ATP 酶（Na+-K+-ATP 酶，NKA），细胞离子平衡的关键调节剂。我还表明 小鼠狼疮中的肾浸润 B 细胞适应了 [Na+] 升高，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 和的药理抑制 NKA g 亚基的基因敲除（此前不知道后者在 B 细胞中表达）导致 减少肾脏 B 细胞浸润并改善蛋白尿。 SLE 患者肾活检中的 B 细胞也 比肾内 T 细胞表达更多的 NKA，表明 NKA 调节的 B 细胞存活途径相同 对人类 SLE 肾炎有效。 Na+ 如何影响细胞死亡途径以及是否调节 B 细胞功能， 例如抗体或细胞因子的产生，是未知的。我假设 Na+ 调节肾内 B 细胞死亡 途径和功能，对其进行剖析将增强对狼疮性肾炎发病机制的了解。瞄准 1，我将研究狼疮与健康对照 B 细胞在暴露于高 Na+ 时经历的死亡途径 离体。在目标 2 中，我将在目标 3 中评估小鼠肾脏 Na+ 环境改变后的 B 细胞功能 我将利用原位成像来定义人类 SLE 肾炎中这些致病细胞的功能景观 活检。这些研究将有助于确定治疗 SLE 肾炎的肾脏特异性靶点。 该奖项的候选人是一位拥有肾脏病学和免疫学双重专业知识的医师科学家。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病和 淋巴细胞-离子相互作用。该奖项将使候选人能够获得来自 耶鲁大学医学院免疫生物学和肾脏病学系，一项重要的研究 机构。全面的职业发展计划，包括生物信息学和统计学课程， RNA杂交和成像技术的获得以及专注于资助和专业发展 稿件准备旨在促进候选人的职业目标，并将通过该奖项来促进。