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:
- 金额:$ 61.82万
- 依托单位:
- 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:
- 关键词:AccelerationAddressAdultAffectAftercareAnimal ModelAntibodiesAntigen-Antibody ComplexAtlasesAttenuatedAutoantibodiesAutoimmune DiseasesAutomobile DrivingBiologicalBiological Response Modifier TherapyBiopsyBloodCRISPR libraryCell CommunicationCell CompartmentationCell physiologyCellsChildClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesComplicationDataDendritic CellsDepositionDevelopmentDiagnosisDiseaseDisease ProgressionDisease remissionEnd stage renal failureFDA approvedFibrosisFlareFlow CytometryFrequenciesFunctional disorderGene SilencingGoalsHeterogeneityHistologicHomeostasisHumanImmuneImmune systemImmunosuppressive AgentsImpairmentIn VitroInfiltrationInflammationInflammatoryInjury to KidneyIntervention StudiesKidneyKidney DiseasesKidney FailureLupusLupus NephritisMacrophageMapsMediatingMedicineMethodsModelingMolecular ProfilingMouse StrainsMusMyelogenousMyeloid CellsNephritisOrganOutcomePathogenicityPathway interactionsPatientsPeripheralPharmaceutical PreparationsPharmacotherapyPhasePhysiologicalPreventionPrognosisProtocols documentationRemission InductionRemission Induction TherapyRenal functionStromal CellsSystemic Lupus ErythematosusTestingTherapeutic InterventionTherapeutic immunosuppressionTimeTissuesbelimumabcytokinedesignhuman datahuman diseasehuman modelimmune cell infiltrateimprovedin vivoindividual patientinterestkidney biopsykidney cellmembermouse modelnew technologynew therapeutic targetnovel therapeutic interventionnovel therapeuticsoutcome predictionpersonalized medicinepreventprogramsrenal damagerepair functionresponders and non-respondersresponsesingle cell analysissingle-cell RNA sequencingstandard of caretherapeutic targettissue repairtranscription 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.
项目摘要
狼疮性肾炎(LN)是系统性红斑狼疮的常见表现,可导致
不可逆肾损害。目前的免疫抑制疗法在超过一半的人中无法逆转疾病。
治疗的患者,只有2种新药已被批准的治疗,这两种药物都只提供适度的
改进.在人类和动物模型中,肾髓样细胞参与LN的肾损伤。
巨噬细胞具有高度可塑性,可以介导促炎和修复功能。因为
骨髓细胞有很多亚群,其中一些随着时间的推移而改变功能,
单细胞对于这些细胞的研究至关重要。第1阶段和第2阶段早期的初步研究
加速药品伙伴关系-SLE(AMP-SLE),其中我们都是成员,已经表明,
LN肾脏中的巨噬细胞的多个亚群类似于小鼠中的髓样亚群,但其功能
这些亚群以及它们是致病的还是保护性的仍然不清楚。肾组织的研究
LN患者的肾脏活检体积小,
患者在其疾病过程中。因此,动物模型,当仔细和严格
使用,是特别有用的解决通过检查人类数据产生的假设。
我们的总体假设是,我们将在LN模型中鉴定与人类相关的髓系细胞亚群,
反映了疾病病理生理学、疾病阶段和对治疗的反应性的差异,
信息将有助于确定治疗干预和直接个性化治疗的新途径。我们
方法的重点是识别和测试人类相关细胞亚群和途径的功能,
体外和体内生理条件下。在目标1中,我们将完成单细胞RNASeq的整合,
分析来自5种不同LN模型的髓样细胞与来自AMP-SLE 2期的髓样细胞,
和独特的巨噬细胞亚群。我们将跟踪外周髓系细胞在转化过程中的命运
从血液进入肾脏,以确定每个子集的肾炎特异性特征以及它们如何
彼此相关。然后,我们将确定是否有一个特定的骨髓细胞谱,
LN患者对标准治疗有反应或无反应。在目标2中,我们将确定如何
在体外和体内,肾髓样细胞与肾基质细胞相互作用。我们将分析肾脏的命运
缓解治疗的人相关小鼠模型中的骨髓细胞(应答和非应答小鼠中)
诱导治疗,以确定修复子集和途径。我们在这里的重点将是两个标准,
治疗和贝利木单抗(抗BAFF),因为这是迄今为止唯一获批用于治疗
LN和预防进一步的肾耀斑。在目标3中,我们将使用CRISPR文库用于体内靶向13种
我们已经在初步研究中确定了转录因子,以筛选新的治疗方法,
保护LN肾脏免于疾病进展、纤维化和终末期肾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Anne Davidson其他文献
Anne Davidson的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Anne Davidson', 18)}}的其他基金
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10470893 - 财政年份:2021
- 资助金额:
$ 61.82万 - 项目类别:
Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE
人 TLR8 诱导 SLE 小鼠模型妊娠失败的机制
- 批准号:
10301657 - 财政年份:2021
- 资助金额:
$ 61.82万 - 项目类别:
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10653079 - 财政年份:2021
- 资助金额:
$ 61.82万 - 项目类别:
Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE
人 TLR8 诱导 SLE 小鼠模型妊娠失败的机制
- 批准号:
10434117 - 财政年份:2021
- 资助金额:
$ 61.82万 - 项目类别:
Induction of lupus-related autoantibodies by TNF inhibitors
TNF 抑制剂诱导狼疮相关自身抗体
- 批准号:
10405223 - 财政年份:2021
- 资助金额:
$ 61.82万 - 项目类别:
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10269999 - 财政年份:2021
- 资助金额:
$ 61.82万 - 项目类别:
Heterogeneous pathways to autoantibody production: implications for prognosis and therapeutic targeting
自身抗体产生的异质途径:对预后和治疗靶向的影响
- 批准号:
10159859 - 财政年份:2019
- 资助金额:
$ 61.82万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 61.82万 - 项目类别:
Research Grant