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Dissecting the heterogeneity and function of myeloid cells in lupus nephritis

剖析狼疮性肾炎骨髓细胞的异质性和功能

基本信息

批准号：
10588862
负责人：
Anne Davidson
金额：
$ 61.82万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
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：
2023-02-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588862
关键词：
Acceleration Address Adult Affect Aftercare Animal Model Antibodies Antigen-Antibody Complex Atlases Attenuated Autoantibodies Autoimmune Diseases Automobile Driving Biological Biological Response Modifier Therapy Biopsy Blood CRISPR library Cell Communication Cell Compartmentation Cell physiology Cells Child Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complication Data Dendritic Cells Deposition Development Diagnosis Disease Disease Progression Disease remission End stage renal failure FDA approved Fibrosis Flare Flow Cytometry Frequencies Functional disorder Gene Silencing Goals Heterogeneity Histologic Homeostasis Human Immune Immune system Immunosuppressive Agents Impairment In Vitro Infiltration Inflammation Inflammatory Injury to Kidney Intervention Studies Kidney Kidney Diseases Kidney Failure Lupus Lupus Nephritis Macrophage Maps Mediating Medicine Methods Modeling Molecular Profiling Mouse Strains Mus Myelogenous Myeloid Cells Nephritis Organ Outcome Pathogenicity Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacotherapy Phase Physiological Prevention Prognosis Protocols documentation Remission Induction Remission Induction Therapy Renal function Stromal Cells Systemic Lupus Erythematosus Testing Therapeutic Intervention Therapeutic immunosuppression Time Tissues belimumab cytokine design human data human disease human model immune cell infiltrate improved in vivo individual patient interest kidney biopsy kidney cell member mouse model new technology new therapeutic target novel therapeutic intervention novel therapeutics outcome prediction personalized medicine prevent programs renal damage repair function responders and non-responders response single cell analysis single-cell RNA sequencing standard of care therapeutic target tissue repair transcription factor

项目摘要

PROJECT SUMMARY Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Current immunosuppressive therapies fail to reverse disease in more than half of treated patients and only 2 new drugs have been approved treatment, both of which confer only modest improvement. Renal myeloid cells are involved in renal injury in LN, both in humans and animal models. Macrophages are highly plastic and can mediate both pro-inflammatory and reparative functions. Because there are so many subsets of myeloid cells and some of them change their function over time, analysis of single cells is crucial to the study of these cells. Initial studies in Phase 1 and early Phase 2 of the Accelerating Medicines Partnerships-SLE (AMP-SLE), of which we are all members, have shown that there are multiple subsets of macrophages in LN kidneys that are analogous to myeloid subsets in mice but the function of these subsets and whether they are pathogenic, or protective is still not known. Study of kidney tissues in LN patients is hampered by the small size of the kidney biopsy and the infrequency of these biopsies in individual patients over the course of their disease. Therefore, animal models, when carefully and rigorously employed, are especially useful for addressing hypotheses generated by examining human data. Our overall hypothesis is that we will identify human-relevant myeloid cell subsets in LN models that reflect differences in disease pathophysiology, disease stage and responsiveness to treatments and that this information will help identify new pathways for therapeutic intervention and direct personalized treatment. Our approach is focused on identifying and testing the function of human-relevant cell subsets and pathways in vitro and under physiologic conditions in vivo. In Aim 1 we will complete the integration of single cell RNASeq analysis of myeloid cells from 5 different models of LN with that from AMP-SLE Phase 2 to map both shared and unique macrophage sub-populations. We will follow the fate of peripheral myeloid cells as they transition from the blood into the kidneys to define how the nephritis-specific profile of each subset and how they are related to each other. We will then determine whether there is a particular myeloid cell profile that is associated with response or non-response of LN patients to standard of care therapy. In Aim 2 we will determine how renal myeloid cells interact with renal stromal cells both in vitro and in vivo. We will analyze the fate of renal myeloid cells (in responder and non-responder mice) in human-relevant mouse models treated with remission induction therapies to identify reparative subsets and pathways. Our focus here will be on both standard of care therapy and on belimumab (anti-BAFF) since this is the only biologic drug so far approved for treatment of LN and for prevention of further renal flares. In Aim 3 we will use CRISPR libraries for in vivo targeting of 13 transcription factors we have identified in preliminary studies to screen for new therapeutic approaches to protect LN kidneys from disease progression, fibrosis, and end stage renal disease.

项目总结