Synovial Biomarkers in Olgoarticular Juvenile Idiopathic Arthritis

描述（由申请人提供）：这是一份为Nemours/ AI杜邦儿童医院（Nemours）的儿科风湿病学家AnneMarie Brescia博士申请K23职业发展奖（CDA）的申请。虽然她在NIAMS/NIH做博士后的两年时间里接受了分子生物学技术方面的培训，但她需要在统计方法、生物信息学和生物标志物开发过程方面的专门培训，以及在资助和科学写作方面的指导。她的短期职业目标是专注于转化研究的培训，并获得所需的工具，以实现她的长期职业目标，成为一名独立的临床转化研究人员，能够帮助塑造未来治疗儿童关节炎的方法。这个CDA将使她从一个主要进行一些研究的临床医生发展成为一个临床科学家，准备好回答一些基本问题，这些问题将转化为更好、更个性化的病人护理。她制定了一个计划，让她通过以下方式获得这些技能：(1)正式的教学指导；(2)研究指导；(3)宾夕法尼亚大学和内穆尔斯大学的教育活动；(4)与该领域的专家合作。她的导师将是Kathleen Sullivan博士（主要导师），儿科风湿病学家，费城儿童医院（CHOP）过敏和免疫学主任；Carlos Rose博士（共同导师），儿科风湿病学家，Nemours风湿病学主任，Nemours IRB主席。她组建了一个咨询委员会，其中还包括爱德华·贝伦斯博士（目前R01资助的研究人员，他带来了儿科风湿病学的内容专业知识）和Birgit Kovacs博士（成人风湿病学家，他带来了广泛的转化研究和生物标志物开发知识）。布雷西亚博士的研究项目主要集中在少关节幼年特发性关节炎（JIA）的致残原因，JIA是儿童最常见的风湿性疾病的最常见亚型。残疾有两个来源，即扩展到多关节病程，称为扩展性少关节疾病，以及与生长改变相关的局部畸形。在整个病程中，持续性少关节炎最多可累及4个关节，而在发病的前6个月，延伸性少关节炎累及5个关节或更多。由于疾病进展会增加致残的风险，因此早期预测这一过程至关重要；不幸的是，目前还没有可靠的临床或实验室预测方法。在该提案中，布雷西亚博士将开发滑膜生物标志物面板，预测从持续性到延展性少关节JIA的疾病进展（目的1）。该项目还将关注JIA成纤维细胞样滑膜细胞在寡关节JIA局部改变生长中的作用（目的2）。滑膜生物标志物将导致更好的风险分层和更有效的靶向治疗。这些目标的完成将导致一项更大的前瞻性研究，在该研究中，在病程早期对滑液样本进行快速评估将用于预测病程，并将对患者进行长期随访，以验证该小组的阳性和阴性预测值。此外，对TGFβ/BMP4信号失调在局部生长改变中的作用的深入了解，将使布雷西亚博士能够研究针对这种表型的干预措施，如果它是修复性的，就增强它，如果它是有害的，就阻断它。这里有一个丰富的学术环境，可以为布雷西亚博士实现她的目标。从这个项目开始，她就与Nemours生物信息学核心的生物统计学家Suzanne McCahan博士密切合作，并将继续这样做。除了研究和教育课程外，她还可以访问Nemours的大量资源，包括转化科学研讨会、期刊俱乐部和风湿病临床会议部门。CHOP的指导为转化研究的合作和专家开辟了途径。Brescia博士将完成宾夕法尼亚大学提供的临床研究证书课程，包括生物统计学、提案开发、科学与伦理行为、生物信息学入门等课程，以及三个基于网络的课程：生物伦理学培训课程、以患者为导向的研究认证课程和HIPAA隐私教育课程，以及合作机构培训计划（CITI）课程。1)负责任的研究行为和2)保护人类受试者。她将受益于Nemours参与几个大型研究合作伙伴关系，特拉华州健康科学联盟（DHSA），特拉华州临床和转化研究计划（DE-CTR）和特拉华州IDeA生物医学研究卓越网络（DE-INBRE），这大大拓宽了可用的智力资源。最后，这个提议的项目非常适合作为Brescia博士在儿科风湿病学领域成熟的转化研究人员的培训工具。此次培训将使Brescia博士能够成功争取到R01资助，进行一项使用滑膜液生物标志物预测新发青少年特发性关节炎病程的前瞻性试验。

DESCRIPTION (provided by applicant): This is an application for a K23 Career Development Award (CDA) for Dr. AnneMarie Brescia, a pediatric rheumatologist at the Nemours/ AI duPont Hospital for Children (Nemours). Although she has had training in molecular biology techniques during her 2 years as a post-doctoral fellow at NIAMS/NIH, she needs specific training in statistical methods, bioinformatics and the process of biomarker development, in addition to guidance on grantsmanship and scientific writing. Her short-term career goals are to focus on training in translational research and acquire the tools needed to achieve her long-term career goals of being an independent clinical translational researcher able to help shape future treatment for children with arthritis. This CDA will allow her to evolve from primarily a clinician conducting some research into a clinician scientist, poised to answer essential questions which will translate into better, more personal, care for patients. She has laid out a plan to allow her o acquire these skill sets through (1) formal didactic instruction; (2) research preceptorships; (3) educational activities at The University of Pennsylvania (Penn) and Nemours; and (4) collaboration with experts in the field. Her mentors will be Dr. Kathleen Sullivan (primary mentor), a pediatric rheumatologist who is Chief of Allergy and Immunology at The Children's Hospital of Philadelphia (CHOP) and Dr. Carlos Rose (co-mentor), a pediatric rheumatologist who is Chief of Rheumatology at Nemours and chairman of the Nemours IRB. She has assembled an advisory committee that also includes Dr. Edward Behrens, a currently R01 funded researcher who brings content expertise in pediatric rheumatology, and Dr. Birgit Kovacs, an adult rheumatologist who brings extensive knowledge of translational research and biomarker development. Dr. Brescia's project focuses on causes of disability in Oligoarticular Juvenile Idiopathic Arthritis (JIA), the most common subtype of the most common rheumatic disease of childhood. Disability results from two sources, namely extension to a polyarticular course, termed extended oligoarticular disease, and local deformities associated with altered growth. Persistent oligoarthritis affects up to 4 joints throughout the disease course while extended oligoarthritis affects a cumulative total of 5 joints or more after the first 6 months of disease. Since disease progression increases the risk for disability, early prediction of this course is essential; unfortunately, no reliable clinical or laboratory predictors have been established. Within this proposal, Dr. Brescia will develop synovial biomarker panels that predict disease progression from persistent to extended oligoarticular JIA (Aim 1). The project will also focus on the role of the JIA fibroblast-like synoviocytes in the localized altered growth seen in oligoarticular JIA (Aim 2). Synovial biomarkers will lead to better risk stratification and more effective targeting of therapeutics. Completion of these aims will lead to a larger, prospective study in which the rapid assessment of synovial fluid samples early in the course of disease will be used to predict disease course and patients will be followed over time to validate the positive and negative predictive values of the panel. In addition, the insight gained into the role of the dysregulated TGFβ/BMP4 signaling in the localized altered growth will allow Dr. Brescia to study interventions that address this phenotype, either enhancing it if it is reparative or blockin it if it is detrimental. There is a rich academic environment available for Dr. Brescia to achieve her goals. From the inception of this project, she has worked closely with Dr. Suzanne McCahan, a biostatistician within Nemours Bioinformatics Core, and will continue to do so. She has access to tremendous resources at Nemours including translational science seminars, journal clubs, and division of rheumatology clinical meetings, in addition to research and education courses. The mentorship at CHOP opens up avenues for collaborations and experts in translational research. Dr. Brescia will complete the Clinical Research Certificate Program offered by Penn, which includes courses in Biostatistics, Proposal Development, Scientific and Ethical Conduct, and Intro to Bioinformatics, in addition to three web-based courses: Bioethics Training Program, Patient-Oriented Research Certification Program and HIPAA Privacy Education Program, in addition to Collaborative Institutional Training Initiative (CITI) programs: 1) Responsible Conduct of Research and 2) Protection of Human Subjects. She will benefit from Nemours participation in several large research partnerships, Delaware Health Sciences Alliance (DHSA), Delaware Clinical and Translational Research Program (DE-CTR), and Delaware IDeA Network of Biomedical Research Excellence (DE-INBRE) that significantly broaden the available intellectual resources available to her. Finally, this proposed project is superbly suited to serve as a training vehicle for Dr. Brescia's maturation as a translational researcher in the field of pediatric rheumatology. This training will allow Dr. Brescia to successfully compete for R01 funding for a prospective trial of using synovial fluid biomarkers to predict course in new onset juvenile idiopathic arthritis.