Spatialomics and quantitative MRI of ischemic injury in a piglet model of Legg-Calve-Perthes disease

项目摘要 这个K 01奖将提供培训和保护的研究时间亚历山德拉阿姆斯特朗，DVM，DACVP，博士 为了实现她的职业目标，成为一名独立资助的具有动物专业知识的研究人员， 发育矫形疾病模型，包括空间组学分析和定量 磁共振成像（MRI）技术。Legg-Calvé-Perthes病（LCPD）是一种发育性 骨科疾病，其发病机制或理想的治疗方案不确定。重要的是 发病机制的关键方面是对股骨近端生长软骨的缺血性损伤： 位于关节面下方的骺生长软骨和股骨内的生长板软骨 脖子这些生长软骨的功能障碍可导致股骨头塌陷和生长停滞 和腿长差异。尽管已知缺血性损伤在LCPD中对软骨的作用， 已经注意到生长软骨对恢复或疾病进展的贡献。到 为了解决这一关键差距，Armstrong博士将使用经过充分验证的LCPD小猪模型来识别差异 与生长障碍相关的生长软骨内表达的基因（Aim 1）和 生长板和骨骺软骨经骺钻孔（目标2），治疗，可能有利于儿童 LCPD引起的生长紊乱空间组学分析确定的模式和途径将是 与组织学特征相关，并与骨骺的定量MRI特征进行比较 软骨，具有鉴定生长软骨损伤的翻译生物标志物的潜力。阿姆斯特朗博士有一个 强大的科学基础，包括肌肉骨骼病理学方面的专业知识，但她需要额外的培训 并致力于发展她的骨科研究计划，解决发病机制的问题， 使用动物模型的儿科骨科疾病。在五年的培训期间，她将获得知识 在发育性骨科疾病的临床管理中，发展新型空间组学的专业知识 方法和分析，在尖端肌肉骨骼MRI技术方面建立强大的知识基础， 在授予写作的重要经验，并在多样性，指导，教学和 领导，这将有利于她作为一个终身教职员工与主要研究为重点的任命。 这项培训将最终在阿姆斯特朗博士实现R 01或同等资金。她将接受指导， 动物模型、矫形外科、肌肉骨骼成像、风湿病学和病理学方面的专家，沿着 通过基因组数据分析的教学培训、实践经验、研讨会/讲习班， 两会阿姆斯特朗博士的工作将集中在UMN兽医临床科学部门， 她的四位导师中有三位阿姆斯特朗博士的K 01训练将充分准备她推出一个独立的 研究生涯的重点是改善受小儿骨科疾病影响的儿童的健康。

PROJECT SUMMARY This K01 award will provide training and protected research time for Alexandra Armstrong, DVM, DACVP, PhD to achieve her career goal of becoming an independently-funded investigator with specialty expertise in animal models of developmental orthopedic diseases, including the application of spatialomic profiling and quantitative magnetic resonance imaging (MRI) techniques. Legg-Calvé-Perthes disease (LCPD) is a developmental orthopaedic disease with uncertainty regarding its pathogenesis or the ideal treatment regimen. Importantly, a key aspect of the pathogenesis is ischemic injury to the growth cartilage in the proximal femur: both the epiphyseal growth cartilage, underlying the articular surface, and the growth plate cartilage, within the femoral neck. Dysfunction of these growth cartilages can contribute to collapse of the femoral head and to growth arrest and leg length discrepancies, respectively. Despite the known role of ischemic injury to cartilage in LCPD, little attention has been paid to the contribution of growth cartilage to either recovery or disease progression. To address this critical gap, Dr. Armstrong will use a well-validated piglet model of LCPD to identify differentially expressed genes within the growth cartilage associated with growth disturbances (Aim 1) and the response of the growth plate and epiphyseal cartilage to transphyseal drilling (Aim 2), a treatment that may benefit children with LCPD-induced growth disturbances. The patterns and pathways identified by spatialomics profiling will be correlated with the histological features and compared to the quantitative MRI features of the epiphyseal cartilage, with the potential to identify translational biomarkers of growth cartilage injury. Dr. Armstrong has a strong scientific foundation, including expertise in musculoskeletal pathology, but she requires additional training and dedicated time to develop her orthopaedic research program addressing questions of pathogenesis of pediatric orthopaedic diseases using animal models. During the five-year training period, she will gain knowledge in the clinical management of developmental orthopaedic disorders, develop expertise in novel spatialomics methods and analysis, develop a strong knowledge base in cutting-edge musculoskeletal MRI techniques, gain crucial experience in grantwriting, and undergo professional development in diversity, mentoring, teaching, and leadership that will benefit her as a tenure-track faculty member with a primarily research-focused appointment. This training will culminate in Dr. Armstrong achieving R01 or equivalent funding. She will be mentored by leading experts in animal models, orthopaedic surgery, musculoskeletal imaging, rheumatology, and pathology, along with didactic training in the analysis of genomic data, hands-on experiences, seminars/workshops, and conferences. Dr. Armstrong’s work will be centered on the UMN Veterinary Clinical Sciences department, where three of her four mentors are situated. Dr. Armstrong’s K01 training will fully prepare her to launch an independent research career focused on improving the health of children affected by pediatric orthopaedic diseases.