Identifying autoimmune associated genes in patrolling monocytes that promote lupus nephritis

识别巡逻单核细胞中促进狼疮肾炎的自身免疫相关基因

基本信息

批准号：
10726991
负责人：
Jessica A Hamerman
金额：
$ 26万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726991
关键词：
Ablation Affect African American population American Asian population Autoimmune Autoimmune Diseases B-Lymphocytes Bioinformatics CRISPR screen CRISPR/Cas technology Cells Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Diagnosis Disease End stage renal failure Exploratory/Developmental Grant FCGR2B gene Future Genes Genetic Risk Genomics Glomerular Capillary Glomerulonephritis Goals Haplotypes Hematopoietic stem cells Hispanic Populations Human Human Genetics ITGAM gene Immune Individual Kidney Kidney Diseases Learning Leukocytes Lupus Lupus Nephritis Macrophage Mediating Methods Modeling Morbidity - disease rate Mus Myeloid Cells Nephritis Organ Pathogenicity Pathway interactions Patients Persons Pharmaceutical Preparations Process Proteins Research Institute Risk Role Source Systemic Lupus Erythematosus T-Lymphocyte TLR7 gene Testing Therapeutic Therapeutically Targetable Validation Variant Woman belimumab cell type chronic autoimmune disease disorder risk experimental study genetic variant genome wide association study genomic locus high reward high risk improved in vivo innate immune mechanisms innovation knockout gene lupus prone mice lupus-like monocyte mortality mouse model new therapeutic target novel novel therapeutic intervention prevent recruit risk variant systemic autoimmune disease transcription factor

项目摘要

PROJECT SUMMARY Lupus nephritis (LN) is seen in ~50% of individuals with the chronic autoimmune disease systemic lupus erythematosus and is a serious cause of morbidity in this disease, with ~10% of SLE cases leading to end stage renal disease within 5 years of diagnosis. LN occurs disproportionately in women of non-European ancestry, including African-Americans, Hispanics and Asians, and despite many years of study, there are few targeted treatments. The recent approval of the first two specific LN therapeutics, belimumab and voclosporin targeting adaptive immune cells (T and B cells), was an important milestone. However, these therapeutics only have ~40% efficacy. Thus, a major challenge in the field is to identify therapies that treat or prevent LN in all patients. There is growing evidence that innate immune cells also contribute to LN. In particular, non-classical, patrolling monocytes have recently been implicated in glomerulonephritis, suggesting that a novel innate immune mechanism through recruitment of patrolling monocytes to the kidney contributes to LN, and that interfering with accumulation of patrolling monocytes early in disease could be therapeutically efficacious. There are no existing therapies that specifically target patrolling monocyte accumulation in the kidney, or other organs, thus, a better understanding of the genes and mechanisms that drive this process holds promise for identifying new therapeutic targets for LN and is the focus of this proposal. Informed by human lupus genetic risk loci, we will define key genes involved in patrolling monocyte accumulation in the kidney in LN. Though many genetic risk variants have been identified as associated with increased risk for SLE, the function of most genes regulated by these variants have not been systematically assessed in innate immune cells such as monocytes. We hypothesize that genes associated with GWAS risk variants may serve as a rich source of regulators of patrolling monocyte accumulation in glomerular capillaries and therefore of LN. To understand how genetic risk loci contribute to patrolling monocyte accumulation in LN, we will use an in vivo CRISPR screen using the TLR7.1 mouse model of lupus- like disease with validation in additional mouse lupus models. Upon completion, we will illuminate genes and pathways that may be targeted by novel therapeutic interventions, which could be used prior to the onset of kidney nephritis. Additionally, risk haplotypes correlated with identified genes could help predict the efficacy of such therapeutic approaches as well as risk for LN.

项目概要狼疮性肾炎 (LN) 见于约 50% 的慢性自身免疫性疾病系统性狼疮患者红斑狼疮，是该疾病发病的一个严重原因，约 10% 的 SLE 病例会进入终末期诊断后 5 年内患有肾脏疾病。 LN 在非欧洲血统的女性中发生率不成比例，包括非裔美国人、西班牙裔和亚洲人，尽管进行了多年的研究，但很少有针对性的治疗。最近批准了前两种特异性 LN 治疗药物贝利尤单抗 (belimumab) 和沃罗孢素 (voclosporin) 靶向药物适应性免疫细胞（T 细胞和 B 细胞）是一个重要的里程碑。然而，这些疗法只有约 40% 功效。因此，该领域的一个主要挑战是确定治疗或预防所有患者 LN 的疗法。那里越来越多的证据表明先天免疫细胞也有助于 LN。特别是非经典的巡逻最近，单核细胞与肾小球肾炎有关，这表明一种新的先天免疫通过招募巡逻单核细胞到肾脏的机制有助于 LN，并且干扰疾病早期巡逻单核细胞的积累可能具有治疗效果。没有现有的专门针对肾脏或其他器官中巡逻单核细胞积聚的疗法，因此，更好的了解驱动这一过程的基因和机制有望确定新的治疗方法 LN 的目标，也是本提案的重点。根据人类狼疮遗传风险位点，我们将定义关键 LN 中涉及肾脏中巡逻单核细胞积累的基因。尽管许多遗传风险变异已被确定与 SLE 风险增加相关，大多数基因的功能受这些变异的调节尚未在单核细胞等先天免疫细胞中进行系统评估。我们假设基因与 GWAS 风险变异相关的可能作为巡逻单核细胞积累调节因子的丰富来源在肾小球毛细血管中，因此在 LN 中。了解遗传风险位点如何有助于巡逻 LN 中的单核细胞积聚，我们将使用狼疮 TLR7.1 小鼠模型进行体内 CRISPR 筛选- 类似疾病，并在其他小鼠狼疮模型中进行了验证。完成后，我们将阐明基因和新的治疗干预措施可能针对的途径，这些干预措施可以在疾病发作之前使用肾肾炎。此外，与已识别基因相关的风险单倍型可以帮助预测此类治疗方法以及 LN 的风险。