权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Monocyte and macrophage polarization in systemic juvenile idiopathic arthritis and macrophage activation syndrome.

系统性幼年特发性关节炎和巨噬细胞活化综合征中的单核细胞和巨噬细胞极化。

基本信息

批准号：
10261417
负责人：
Grant Sanford Schulert
金额：
$ 16.85万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-07 至 2022-07-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY / ABSTRACT Systemic juvenile idiopathic arthritis is a severe inflammatory disease of childhood conferring significant risk for fatal complications including Macrophage Activation Syndrome (MAS). The phenotype and function of the key effector monocytes and macrophages in systemic JIA remains unclear. These cells adopt distinct polarization states based on specific activating signals, modified by microRNA to “fine-tune” these transcriptional responses. Circulating monocytes in systemic JIA appear to display a unique mixed polarization phenotype, and little is known regarding how tissue resident macrophages are further altered during emergence of MAS. Notably, despite effective treatment children with systemic JIA remain at risk for MAS. Thus, there is a critical need to characterize the phenotype of monocytes and tissue macrophages in systemic JIA, and particularly how they contribute to emergence of MAS. In the absence of such knowledge, developing novel strategies to effectively prevent and treat MAS will remain a formidable challenge. The objective in this application is to define polarization-specific gene expression signatures and functional roles of microRNA in monocytes and macrophages from children with systemic JIA and a mouse model of systemic JIA/MAS. Our central hypothesis is monocytes from children with systemic JIA have a distinct polarized pattern which is regulated by microRNA, and further dysregulated during MAS. The research plan described in this application has three Specific Aims: to define polarization-specific and single-cell gene expression profiles in peripheral monocytes and bone marrow macrophages from systemic JIA and MAS patients (Aim 1), to identify specific molecular pathways targeted by microRNA that are essential for monocyte and macrophage polarization in these disorders (Aim 2), and to determine gene expression signatures and microRNA-mediated functions of polarized myeloid populations in a mouse model of MAS (Aim 3). These independent and complementary aims will utilize emerging technologies such as microRNA expression profiling and single-cell RNAseq to define the molecular control of polarization-specific transcriptional signatures in monocytes and macrophages in children with systemic JIA and MAS. Together these findings are expected to have positive translational impact, through providing new targets to modulate inflammation in systemic JIA and impact the risk for MAS. Dr. Grant Schulert is currently an Instructor of Pediatrics in the Division of Rheumatology at Cincinnati Children's Hospital Medical Center. Dr. Schulert's long-term goal is to develop an independent research career as a pediatric rheumatologist focused on the pathogenesis and novel treatment approaches for inflammatory disorders. In the completion of these proposed aims, Dr. Schulert will draw upon greater than 10 years' experience studying inflammation and innate immunity, but will also gain new skills and knowledge in the areas of functional genomics, microRNA biology and animal models of inflammatory disorders. Dr. Schulert and his primary mentor, Dr. Alexei Grom, have developed a comprehensive career development plan with four key components: laboratory experimentation; mentored oversight guided by his mentorship committee; leadership and skills building through the CCHMC Leadership Foundations Program and other workshops; and academic and professional development through scientific meetings, intramural conferences and the CCHMC “K Club”. His career development will be guided by an interdisciplinary mentorship committee chaired by Dr. Grom. Additional members of Dr. Schulert's mentorship committee will facilitate the acquisition of new skills and knowledge throughout the award period, while serving as key collaborators for the proposed research aims. The environment at CCHMC is highly supportive of Dr. Schulert's development in this key early stage of his research career. This institution offers a variety of resources both physical and intellectual to support his career development, and CCHMC has committed to protecting at least 75% of his time for research during the award period. CCHMC has been the home of the premier training and research program in pediatric rheumatology for several decades. The divisional research portfolio is quite diverse, spanning from genomic in juvenile idiopathic arthritis (JIA) to the discovery of organ-specific biomarkers for childhood-onset lupus to international clinical trials of new drug targets. Collectively, completion of the proposed studies, aided by the mentoring committee and with the outstanding institutional environment including shared core facilities available at Cincinnati Children's Hospital Medical Center, will provide the ideal environment for Dr. Schulert to achieve his career goal of becoming an independent investigator within Pediatric Rheumatology.

项目摘要/摘要系统性幼年特发性关节炎是一种严重的儿童期炎症性疾病。包括巨噬细胞激活综合征(MAS)在内的致命并发症的风险。细胞的表型和功能系统性JIA的关键效应细胞是单核细胞和巨噬细胞，目前尚不清楚。这些细胞采用不同的基于特定激活信号的极化状态，由microRNA进行修改以对其进行微调转录反应。系统性JIA患者循环单核细胞表现出独特的混合极化表型，关于组织驻留的巨噬细胞是如何在 MAS的出现。值得注意的是，尽管进行了有效的治疗，患有系统性JIA的儿童仍然面临着MAS的风险。因此，迫切需要研究系统性红斑狼疮中单核细胞和组织巨噬细胞的表型。尤其是它们对MAS的出现做出了哪些贡献。在缺乏这样的知识的情况下，发展有效预防和治疗MAS的新战略仍将是一项艰巨的挑战。这件事的目的是应用是确定极化特异的基因表达特征和microRNA在系统性JIA患儿和系统性JIA/MAS小鼠模型的单核细胞和巨噬细胞。我们的中心假说是系统性JIA患儿的单核细胞有明显的极化模式，即受microRNA调控，并在MAS过程中进一步失调。此申请表中描述的研究计划有三个具体目标：确定外周极化特异性和单细胞基因表达谱系统性JIA和MAS患者的单核细胞和骨髓巨噬细胞(目标1)鉴定特异性 MicroRNA靶向的单核细胞和巨噬细胞极化所必需的分子通路这些障碍(目标2)，并确定基因表达特征和microRNA介导的功能 MAS小鼠模型中的极化髓系群体(目标3)。这些都是独立的和互补的 AIMS将利用MicroRNA表达谱和单细胞RNAseq等新兴技术来确定单核细胞和巨噬细胞极化特异性转录信号的分子控制患有系统性JIA和MAS的儿童。总而言之，这些发现有望对翻译产生积极的影响影响，通过提供新的靶点来调节系统性JIA的炎症和影响MAS的风险。格兰特·舒勒特医生目前是辛辛那提大学风湿科儿科讲师儿童医院医疗中心。舒勒特博士的长期目标是发展独立的研究事业作为一名专注于炎症性疾病的发病机制和新的治疗方法的儿科风湿学家精神错乱。在完成这些拟议的目标时，舒勒特博士将利用超过10年的时间有研究炎症和先天免疫的经验，但也会在这些领域获得新的技能和知识功能基因组学、微RNA生物学和炎症性疾病的动物模型。舒勒特博士和他的首席导师阿列克谢·格罗姆博士制定了一项全面的职业发展计划，包括四个关键组成部分：实验室实验；他的指导委员会指导的指导监督；领导力通过CCHMC领导力基础计划和其他研讨会进行技能建设；以及学术通过科学会议、校内会议和CCHMC“K俱乐部”促进专业发展。他的职业发展将由一个由格罗姆博士担任主席的跨学科指导委员会指导。舒勒特博士导师委员会的更多成员将促进新技能的获得和在整个获奖期间提供知识，同时担任拟议研究目标的主要合作者。 CCHMC的环境高度支持Schulert博士在这一关键的早期阶段的发展他的研究生涯。这个机构提供了各种物质和智力资源来支持他的职业发展，CCHMC承诺保护他至少75%的时间在获奖期。CCHMC是首屈一指的儿科培训和研究计划的发源地风湿病已经有几十年了。该部门的研究组合相当多样化，从基因组到幼年特发性关节炎(JIA)对儿童狼疮器官特异性生物标志物的发现新药靶点的国际临床试验。共同完成拟议的研究，在指导委员会和出色的机构环境，包括辛辛那提儿童医院提供的共享核心设施医疗中心将为舒勒特博士实现成为一名医生的职业目标提供理想的环境儿科风湿科的独立调查员。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The IL-18/IFNγ axis in systemic JIA and MAS-new answers, more questions.

系统性 JIA 和 MAS 中的 IL-18/IFNγ 轴-新答案，更多问题。

DOI：
10.1093/rheumatology/keab342
发表时间：
2021
期刊：
Rheumatology (Oxford, England)
影响因子：
0
作者：
Schulert,GrantS
通讯作者：
Schulert,GrantS

Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study.

DOI：
10.1016/s2665-9913(21)00139-9
发表时间：
2021-08
期刊：
The Lancet. Rheumatology
影响因子：
0
作者：
Rodriguez-Smith JJ;Verweyen EL;Clay GM;Esteban YM;de Loizaga SR;Baker EJ;Do T;Dhakal S;Lang SM;Grom AA;Grier D;Schulert GS
通讯作者：
Schulert GS

Population-level single-cell genomics reveals conserved gene programs in systemic juvenile idiopathic arthritis.

DOI：
10.1172/jci166741
发表时间：
2023-11-15
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Verweyen, Emely L.;Thakkar, Kairavee;Dhakal, Sanjeev;Baker, Elizabeth;Chetal, Kashish;Schnell, Daniel;Canna, Scott;Grom, Alexei A.;Salomonis, Nathan;Schulert, Grant S.
通讯作者：
Schulert, Grant S.

Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis.