Cellular Dynamics at the Synovium-Bone interface in RA

RA 滑膜-骨界面的细胞动力学

基本信息

批准号：
10200988
负责人：
Jennifer Howitt Anolik
金额：
$ 10万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200988
关键词：
3-Dimensional Anatomy Area B-Cell Activation B-Lymphocytes Bioinformatics Biological Biological Markers Biological Response Modifier Therapy Biopsy Biopsy Specimen Bone Marrow Bone Resorption Bone Tissue CD14 gene CD19 gene CD4 Positive T Lymphocytes Cell Communication Cell physiology Cells Clinical Collaborations Computer software Cytokine Activation Cytokine Network Pathway Data Data Management Resources Degenerative polyarthritis Disease Doppler Ultrasound Equilibrium Failure Functional disorder Goals Histology Homeostasis Hypersensitivity Image Image Analysis Immune Immunohistochemistry Immunology Individual Infiltration Informatics Joints Laboratories Lasers Lead Link Location Lymphatic Lymphocyte Mediating Medicine Methods Musculoskeletal Musculoskeletal Diseases Nature Needle biopsy procedure Operative Surgical Procedures Orthopedics Osteoblasts Osteoclasts Osteogenesis Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Population Procedures RNA RNA Sequences Research Rheumatoid Arthritis Rheumatology Role Sampling Seminal Signal Pathway Site Sorting - Cell Movement Specimen Standardization Stream Sushi Domain Synovial Membrane T-Lymphocyte Techniques Technology Tissues Ultrasonography Universities bone bone cell bone erosion cohort digital effective therapy imaging system individualized medicine insight joint destruction joint injury monocyte new technology novel patient population patient stratification patient subsets peripheral blood prospective public health relevance response single-cell RNA sequencing subchondral bone tool transcriptome transcriptome sequencing treatment response treatment strategy validation studies whole slide imaging

项目摘要

DESCRIPTION (provided by applicant): The focus of this Combined Clinical and Technology Research Site (CTRS) application is to apply novel histomorphometric and transcriptome analytics to define the interplay between lymphocytes (B cells and T cells) and bone homeostasis in rheumatoid arthritis (RA) within target tissue and well-characterized patient populations. We plan to develop and optimize strategies to categorize subsets of disease, define biomarkers of treatment response, and identify novel treatment targets. Research to date in RA has focused on defining abnormalities in individual immune cell populations or signaling pathways involved in osteoclast (OC) differentiation and activation or osteoblast (OB) function, but very few groups have provided an integrated assessment of the multiple relevant cell populations in the disease and the interactions between the lymphocyte and bone compartments in target tissue. Although prior approaches have yielded important clues regarding immune pathogenesis, major limitations in the field include the lack of biomarkers to target appropriate treatment strategies and the failure of currently available treatments to achieve low disease activity and/or limit progressive joint damage in the majority of patients. Our group has made multiple observations linking B cells to joint damage including the efficacy of B cell depletion as a treatment and the presence of B cell aggregates in rarely studied target tissue including the synovium, subchondral bone, and bone marrow (BM) where OBs and OCs develop, associated with T cell and OC activation and more recently OB dysfunction. Additional seminal observations by our group have defined monocyte dysfunction in RA and characterized key down-stream signaling pathways in OC differentiation and activation. However, the role and precise mechanisms of aberrant B-T cell interactions and other pathways (including monocyte and cytokine activation) in mediating joint destruction in the target tissue are relatively unexplored and a ripe area for identification of new treatment targets. This assessment to date has been hampered by lack of access to relevant target tissue and the need for novel technologic approaches to better define cellular and cytokine networks. We can surmount these limitations given a unique collaboration between Rheumatology and Orthopedics with access to unprecedented surgical and biopsy samples from untreated RA patients and powerful technologies within the Center for Musculoskeletal Research (CMSR) at the University of Rochester (UR) already well-validated for the study of musculoskeletal diseases. In this proposal we will (1) Integrate clinical, laboratory, and ultra-sound (US) data on treated and untreated RA patients and establish optimal methods for acquisition of synovial tissue by US-guided needle biopsy, (2) Characterize the localization of relevant immune and bone cells in the joint using novel histomorphometric tools for automated quantitation, and (3) Define cell function by RNA sequencing of discrete sorted and captured cell populations in synovium. The powerful dual approach of characterizing the location of key cell populations at the bone-pannus junction and defining cell function within this 3D milieu using novel histomorphometric tools and RNA sequencing of discrete cell populations will better reflect underlying disease pathogenesis, allowing more precise patient stratification and identification of novel targets.

描述（由应用提供）：该组合的临床和技术研究站点（CTRS）应用的重点是应用新型的组织形态计量学和转录组分析来定义淋巴细胞（B细胞和T细胞）与类风湿性关节炎（RA）中淋巴细胞（B细胞和T细胞）之间的相互作用（RA）在靶组织组织和良好的患者中的相互作用。我们计划制定和优化策略以分类疾病亚集，定义治疗反应的生物标志物并确定新颖的治疗靶标。迄今为止在RA的研究集中在定义单个免疫细胞群体的异常或与破骨细胞（OC）分化和激活或成骨细胞（OB）功能有关的单个免疫细胞群体或信号通路的异常，但是很少有群体对疾病中的多个相关细胞群体进行了综合评估，以及淋巴细胞和骨骼组合中的相互作用。尽管先前的方法已经对免疫发病机理产生了重要的线索，但该领域的主要局限性包括缺乏针对适当治疗策略的生物标志物以及目前可用的治疗失败以实现低疾病活动和/或限制大多数患者的渐进性关节损害。我们的小组已经进行了多次观察，将B细胞与关节损伤联系起来，包括B细胞部署作为一种治疗的有效性以及在很少研究的靶向组织中的B细胞聚集物的存在，包括滑膜，软骨下骨和骨髓（BM），在该目标组织中，观察和OCS与T细胞和OC相关的OBS和OCS与T细胞和OC激活以及更近的OB功能相关。我们组的其他第二个观察结果定义了RA中的单核细胞功能障碍，并表征了OC分化和激活中的钥匙下游信号通路。然而，异常B-T细胞相互作用以及其他途径（包括单核细胞和细胞因子激活）在靶向组织中的关节破坏中的作用和精确机制相对出乎意料，并且是鉴定新治疗靶标的成熟区域。迄今为止，由于缺乏获得相关目标组织的访问以及对更好地定义细胞和细胞因子网络的新型技术方法的需求，这项评估受到了阻碍。我们可以克服这些局限性，鉴于流变学和骨科之间的独特合作，并从未经治疗的RA患者那里获得了前所未有的手术和活检样本，以及在罗切斯特大学（Universion of Rochester）（University of Rochester（UNI）的肌肉骨骼研究中心（CMSR）内的强大技术（UR）（UR）已经妥善研究了肌肉骨骼的研究。在这项提案中，我们将（1）整合有关治疗和未经处理的RA患者的临床，实验室和超声（US）数据，并通过US引导的针头活检来建立最佳的方法，以获取滑膜组织，（2）表征相关免疫和骨细胞在相关的免疫细胞中的定位，该定位是使用新型小组进行定量和（3）的定量定量和（3）的（3）定义的（3），以及（3），以及（3）。在滑膜中捕获的细胞群。表征关键细胞群体在骨 - 大通结处的位置的强大双重方法，并使用新型的组织形态计量学工具和离散细胞群体的RNA测序在此3D环境中定义细胞功能，将更好地反映潜在的疾病发病机理，从而使患者的分层更为精确。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers.

DOI：
10.4049/jimmunol.1700354
发表时间：
2017-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Bird AK;Chang M;Barnard J;Goldman BI;Meednu N;Rangel-Moreno J;Anolik JH
通讯作者：
Anolik JH

Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis.

DOI：
10.1002/art.39489
发表时间：
2016-04
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
0
作者：
Meednu N;Zhang H;Owen T;Sun W;Wang V;Cistrone C;Rangel-Moreno J;Xing L;Anolik JH
通讯作者：
Anolik JH

New insights into B cell biology in systemic lupus erythematosus and Sjögren's syndrome.

DOI：
10.1097/bor.0000000000000201
发表时间：
2015-09
期刊：
Current opinion in rheumatology
影响因子：
5.1
作者：
Bird AK;Meednu N;Anolik JH
通讯作者：
Anolik JH

B Cell Activation and Plasma Cell Differentiation Are Promoted by IFN-λ in Systemic Lupus Erythematosus.

DOI：
10.4049/jimmunol.2100339
发表时间：
2021-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Barnas JL;Albrecht J;Meednu N;Alzamareh DF;Baker C;McDavid A;Looney RJ;Anolik JH
通讯作者：
Anolik JH

Small Molecule Inhibitors of Nuclear Export and the Amelioration of Lupus by Modulation of Plasma Cell Generation and Survival.

DOI：
10.1002/art.42128
发表时间：
2022-08
期刊：
ARTHRITIS & RHEUMATOLOGY
影响因子：
13.3
作者：
Rangel-Moreno, Javier;Garcia-Hernandez, Maria de la Luz;Owen, Teresa;Barnard, Jennifer;Becerril-Villanueva, Enrique;Kashyap, Trinayan;Argueta, Christian;Gamboa-Dominguez, Armando;Tamir, Sharon;Landesman, Yosef;Goldman, Bruce I.;Ritchlin, Christopher T.;Anolik, Jennifer H.
通讯作者：
Anolik, Jennifer H.