Tissue research in childhood inflammatory arthritis (TRICIA consortium)

儿童炎症性关节炎的组织研究（TRICIA 联盟）

• 批准号: MR/W028557/1
• 负责人: Adam Croft
• 金额: $ 138.62万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW028557%2F1
• 关键词: Tissue; research; childhood; inflammatory; arthritis

Childhood arthritis affects 1 in 1000 children and young people and is called Juvenile Idiopathic Arthritis (JIA). We now know that early and intensive treatment of JIA reduces the risk of long-term joint damage and increases the likelihood that arthritis will be sufficiently controlled to allow treatment to be stopped in the future. However, JIA can present in many different ways: while some children already have severe arthritis at the time of diagnosis, others have a mild form of arthritis limited to the involvement of a small number of joints. Some of these children will go on to develop severe arthritis, while in others, the arthritis improves with only simple medications such as ibuprofen. At present we cannot predict which children will go on to develop severe arthritis or which children will respond to certain types of drugs. Thus, a major barrier to developing a 'precision approach' to treatment in JIA is the ability to identify which children require treatment and who is likely to respond to which type of drug. To date, the majority of research in JIA to address this unmet need has been carried out on either blood samples or joint fluid, due to difficulties in accessing the site of the disease itself - the synovial tissue (joint lining), and therefore do not reflect accurately pathology in the joint. We have pioneered the use of a minimally invasive, safe and well-tolerated technique to obtain small pieces of synovial tissue or 'synovial tissue biopsies' in adults with rheumatoid arthritis (RA). These studies have transformed our understanding of disease in RA and led to new therapy targets and biopsy driven pathology led treatment stratification trials. No such studies exist in JIA. We are currently performing the first synovial biopsy-based studies in JIA as part of a collaborative network between Birmingham, University College London and Oxford (MAPJAG study). While JIA is phenotypically and biologically distinct from RA, the availability of safe, effective, synovial biopsy techniques that can be repeated longitudinally in routine NHS surroundings has the potential to deliver a paradigm shift in our understanding of disease pathology, biomarker discovery and the development of therapeutic targets in JIA. The rarity of JIA compared to RA means it is necessary to expand our existing network to support studies that are sufficiently powered, with appropriate numbers of cases to address important research questions. In this partnership we propose to build capacity within UK paediatric rheumatology to perform ultrasound-guided synovial tissue biopsies as part of clinical research and bring these studies together to form a unique Consortium, called the Tissue Research in Childhood Inflammatory Arthritis (TRICIA). TRICIA will work with all the main stakeholders including clinical and research collaborators, as well as families and patients whose lives are affected by JIA. Importantly, the partnership will form collaborations with other key UK and international consortia initiatives to streamline precision medicine strategies in JIA.The key aspects of the work planned in the TRICIA Consortium are to: 1. Support the establishment of peadiatric synovial tissue biopsy programs at new centres.2. Provide training and expertise in performing synovial tissue biopsies in children and young people with arthritis.3. Collect data on the acceptability, tolerability and safety of the biopsy procedure in a paediatric population.4. Have a consistent approach to collecting clinical data linked to biological samples. 5. Agree to collect data and tissue samples in the same way in the future.6. Design and agree a way to share data within a common platform that can be used by researchers to better understand arthritis.

儿童关节炎影响1/1000的儿童和青少年，被称为青少年特发性关节炎（JIA）。我们现在知道，JIA的早期和强化治疗可以降低长期关节损伤的风险，并增加关节炎得到充分控制的可能性，以便将来停止治疗。然而，JIA可以以许多不同的方式出现：虽然一些儿童在诊断时已经患有严重的关节炎，但其他儿童的关节炎仅限于少数关节。这些儿童中的一些会继续发展严重的关节炎，而在其他人中，关节炎仅用布洛芬等简单药物即可改善。目前，我们无法预测哪些儿童会继续发展为严重的关节炎，或者哪些儿童会对某些类型的药物产生反应。因此，在JIA中开发“精确方法”的主要障碍是识别哪些儿童需要治疗以及哪些儿童可能对哪种类型的药物有反应的能力。迄今为止，JIA中解决这一未满足需求的大多数研究都是在血液样本或关节液中进行的，因为难以进入疾病本身的部位-滑膜组织（关节衬里），因此不能准确反映关节的病理学。我们率先使用微创，安全和耐受性良好的技术来获得成人类风湿关节炎（RA）患者的小块滑膜组织或“滑膜组织活检”。这些研究改变了我们对RA疾病的理解，并导致新的治疗靶点和活检驱动的病理学引导的治疗分层试验。在JIA中不存在此类研究。作为伯明翰、伦敦大学学院和牛津大学合作网络的一部分，我们目前正在JIA进行第一项基于滑膜活检的研究（MAPJAG研究）。虽然JIA在表型和生物学上与RA不同，但可以在常规NHS环境中纵向重复的安全，有效的滑膜活检技术的可用性有可能在我们对JIA疾病病理学，生物标志物发现和治疗靶点开发的理解中提供范式转变。与RA相比，JIA的罕见性意味着有必要扩大我们现有的网络，以支持足够有力的研究，并提供适当数量的病例来解决重要的研究问题。在这种伙伴关系中，我们建议在英国儿科风湿病学中建立能力，以进行超声引导的滑膜组织活检作为临床研究的一部分，并将这些研究结合在一起，形成一个独特的联盟，称为儿童炎症性关节炎组织研究（TRICIA）。TRICIA将与所有主要利益相关者合作，包括临床和研究合作者，以及生活受到JIA影响的家庭和患者。重要的是，该合作伙伴关系将与其他主要的英国和国际财团合作，以简化JIA的精准医疗战略。TRICIA财团计划的工作的关键方面是：1.支持在新中心建立儿童滑膜组织活检项目。为患有关节炎的儿童和年轻人提供滑膜组织活检的培训和专业知识。收集儿科人群中活检程序的可接受性、耐受性和安全性数据。采用一致的方法收集与生物样本相关的临床数据。5.同意今后以同样的方式收集数据和组织样本。设计并商定一种在通用平台内共享数据的方法，以便研究人员更好地了解关节炎。

项目成果

Are the origins of adult arthritis seeded during embryonic development?

成人关节炎的起源是在胚胎发育过程中播种的吗？

• DOI: 10.1038/s41584-023-00911-x
• 发表时间: 2023
• 期刊: Nature reviews. Rheumatology
• 作者: Hackland A

All fibroblasts are equal, but some are more equal than others.

所有成纤维细胞都是平等的，但有些成纤维细胞比其他成纤维细胞更平等。

• DOI: 10.1038/s41584-024-01097-6
• 发表时间: 2024
• 期刊: Nature reviews. Rheumatology
• 作者: Bolton C

Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies.

• DOI: 10.1158/2159-8290.cd-22-0199
• 发表时间: 2023-02-06
• 期刊: CANCER DISCOVERY
• 影响因子: 28.2
• 作者: Khan, Abdullah O.;Rodriguez-Romera, Antonio;Reyat, Jasmeet S.;Olijnik, Aude-Anais;Colombo, Michela;Wang, Guanlin;Wen, Wei Xiong;Sousos, Nikolaos;Murphy, Lauren C.;Grygielska, Beata;Perrella, Gina;Mahony, Christopher B.;Ling, Rebecca E.;Elliott, Natalina E.;Karali, Christina Simoglou;Stone, Andrew P.;Kemble, Samuel;Cutler, Emily A.;Fielding, Adele K.;Croft, Adam P.;Bassett, David;Poologasundarampillai, Gowsihan;Roy, Anindita;Gooding, Sarah;Rayes, Julie;Machlus, Kellie R.;Psaila, Bethan
• 通讯作者: Psaila, Bethan

Towards molecular-pathology informed clinical trials in childhood arthritis to achieve precision medicine in juvenile idiopathic arthritis.

• DOI: 10.1136/ard-2022-222553
• 发表时间: 2023-04
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4