Autoimmunity-Associated B Cells in Lupus Nephritis

狼疮性肾炎中自身免疫相关的 B 细胞

• 批准号: 10582053
• 负责人: Jennifer Lynn Barnas
• 金额: $ 19.22万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-16 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582053
• 关键词: Autoantibodies; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biometry; Cells; Cellular biology; Data; Development; Development Plans; Disease; Doctor of Philosophy; Epigenetic Process; Funding; Gene Expression; Immune; In Vitro; Interferon Type II; Interferons; Kidney; Lupus; Lupus Nephritis; Maps; Mentorship; Molecular; Pathway interactions; Patients; Plasma Cells; Research; Signal Transduction; Systemic Lupus Erythematosus; Techniques; Tissue Sample; Tissues; United States National Institutes of Health; Universities; Work; autoreactivity; career development; clinically relevant; cytokine; epigenetic regulation; epigenomics; experience; interleukin-21; large datasets; new therapeutic target; novel therapeutic intervention; plasma cell development; plasma cell differentiation; programs; research and development; single cell analysis; skills; transcriptomics

PROJECT SUMMARY/ABSTRACT This proposal details a five-year research and career development plan with a scientific focus on autoimmunity-associated B cells (ABC), a subset of cells that is expanded during lupus disease activity and can differentiate into autoantibody-producing plasma cells (PC). These cells are found in the kidneys of lupus nephritis patients. The long-term objective of the study is to understand signals that regulate the development of ABC and autoreactive PC in lupus nephritis patients in hopes of identifying new therapeutic targets. Preliminary data suggest that ABC develop after B cell activation in the presence of interferon-gamma (IFN-γ) and interleukin 21. ABC are hyper-responsive to type III interferon (IFN-λ). PC differentiation can be promoted by IFN-λ in healthy B cells. In this application, Aim 1 will determine how interferon lambda (IFN-λ) promotes ABC differentiation to PC by examining epigenetic and gene expression changes in B cells treated with IFN-λ. Aim 2 will define the relationships between ABC and their cellular neighbors in the renal microenvironment. In particular, the developmental relationship between ABC and other B cells in the kidneys of lupus nephritis patients will be examined using transcriptomic approaches. A gene expression map of the cellular neighbors of ABC and PC in the lupus nephritis renal microenvironment will be created using spatial transcriptomic analysis. This will identify factors that may be promoting the development of autoimmunity in lupus nephritis. This project will allow Dr. Jennifer Barnas, MD, PhD to develop her skill set in molecular techniques such epigenomics, spatial and single cell transcriptomics and biostatistical anlaysis of these large data sets under the mentorship of Dr. Jennifer Anolik, an expert in lupus B cell biology, Dr. Martha Susiarjo, an expert in epigenetic regulation of disease, and Dr. Andrew McDavid, a computational biologist with extensive experience in single- cell analysis of immune cells. Dr. Barnas will use these techniques to develop an independent research program at University of Rochester and apply for NIH R01 funding to study B cell activation pathways and PC development in autoimmune disease. This work will inform the origin of ABCs and establish whether pathways revealed by in vitro studies are functioning in clinically relevant tissue samples.

项目摘要/摘要 该提案详细介绍了一项五年研究和职业发展计划，其科学重点是 自身免疫相关的B细胞（ABC），是在狼疮疾病活动期间扩增的细胞亚群， 可分化为产生自身抗体的浆细胞（PC）。这些细胞存在于狼疮患者的肾脏中 肾炎患者 这项研究的长期目标是了解调节ABC发展的信号， 自身反应性PC在狼疮性肾炎患者中的应用，希望找到新的治疗靶点。初步数据 表明在干扰素-γ（IFN-γ）和白细胞介素存在下，在B细胞活化后ABC发展 21. ABC对III型干扰素（IFN-λ）有高度反应。IFN-λ可促进PC分化， 健康的B细胞。在本申请中，目标1将确定干扰素λ（IFN-λ）如何促进ABC 通过检查用IFN-λ处理的B细胞中的表观遗传和基因表达变化来观察向PC的分化。目的 2将定义ABC和它们在肾脏微环境中的细胞邻居之间的关系。在 特别是狼疮性肾炎肾脏中ABC和其他B细胞之间的发育关系 将使用转录组学方法检查患者。细胞邻居的基因表达图 ABC和PC在狼疮肾炎肾微环境中的表达将使用空间转录组学方法建立。 分析.这将确定可能促进狼疮性肾炎自身免疫发展的因素。 该项目将允许博士詹妮弗·巴纳斯，医学博士，博士发展她的技能，在分子技术， 表观基因组学，空间和单细胞转录组学和生物统计分析这些大型数据集下， 导师詹妮弗Anolik博士，狼疮B细胞生物学专家，玛莎Susiarjo博士，表观遗传学专家 和安德鲁·麦克大卫博士，一位在单细胞免疫方面有着丰富经验的计算生物学家， 免疫细胞的细胞分析巴纳斯博士将利用这些技术开发一个独立的研究项目 在罗切斯特大学，并申请NIH R 01基金，研究B细胞活化途径和PC发育 自身免疫性疾病这项工作将告知ABC的起源，并确定是否通过基因表达揭示的途径。 体外研究在临床相关的组织样品中起作用。