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

• 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
• 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

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.

项目摘要 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 是该病的一个严重发病原因，约10%的SLE病例导致终末期 诊断后5年内的肾脏疾病。LN在非欧洲血统的女性中不成比例地发生， 包括非洲裔美国人，西班牙裔和亚洲人，尽管多年的研究， 治疗。最近批准的前两个特定的LN治疗药物，贝利木单抗和voclosporin靶向 适应性免疫细胞（T和B细胞）的出现是一个重要的里程碑。然而，这些疗法仅具有~40% 功效因此，该领域的主要挑战是确定治疗或预防所有患者的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， 单核细胞最近被牵连在肾小球肾炎，这表明，一种新的先天性免疫， 通过募集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是治疗有效的。没有现有 特别针对肾脏或其他器官中巡逻单核细胞积聚的治疗，因此， 了解驱动这一过程的基因和机制， 这也是本次提案的重点。根据人类狼疮遗传风险位点，我们将定义关键 参与巡逻LN患者肾脏单核细胞积聚的基因。尽管许多遗传风险变异 已被确定为与SLE风险增加有关，大多数基因的功能受这些变异体的调节 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风险变异相关的一个基因可能作为巡逻单核细胞积聚的调节剂的丰富来源， 肾小球毛细血管和LN。了解遗传风险位点如何有助于巡逻 为了减少LN中单核细胞的积累，我们将使用狼疮的TLR7.1小鼠模型进行体内CRISPR筛选， 在其他小鼠狼疮模型中得到验证。完成后，我们将照亮基因， 可能被新的治疗干预所靶向的途径，这些干预可以在疾病发作之前使用。 肾性肾炎此外，与已鉴定基因相关的风险单倍型可以帮助预测 这种治疗方法以及LN的风险。