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

项目概要 该 K01 奖项将为 Alexandra Armstrong（DVM、DACVP、PhD）提供培训和受保护的研究时间 实现她的职业目标，成为一名拥有动物专业知识的独立资助的调查员 发育性骨科疾病模型，包括空间组学分析和定量的应用 磁共振成像（MRI）技术。 Legg-Calvé-Perthes 病 (LCPD) 是一种发育性疾病 其发病机制或理想治疗方案不确定的骨科疾病。重要的是，一个 发病机制的关键方面是股骨近端生长软骨的缺血性损伤： 骨骺生长软骨位于关节面下方，生长板软骨位于股骨内 脖子。这些生长软骨的功能障碍可能导致股骨头塌陷和生长停滞 和腿长差异。尽管软骨缺血性损伤在 LCPD 中的作用已为人所知，但很少有人知道 人们关注生长软骨对恢复或疾病进展的贡献。至 为了解决这一关键差距，阿姆斯特朗博士将使用经过充分验证的 LCPD 仔猪模型来差异识别 生长软骨内与生长障碍（目标 1）相关的表达基因以及 生长板和骨骺软骨转骺钻孔（目标 2），一种可能使儿童受益的治疗方法 LCPD 引起的生长障碍。通过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，具有识别生长软骨损伤的转化生物标志物的潜力。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 并投入时间开发她的骨科研究计划，解决骨科疾病的发病机制问题 使用动物模型研究小儿骨科疾病。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，发展新型空间组学方面的专业知识 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，获得 拨款写作方面的重要经验，并在多样性、指导、教学和 作为一名主要以研究为重点的任命的终身教授，她的领导能力将使她受益。 该培训最终将使阿姆斯特朗博士获得 R01 或同等资助。她将得到领导的指导 动物模型、骨科手术、肌肉骨骼成像、风湿病学和病理学方面的专家，以及 通过基因组数据分析、实践经验、研讨会/讲习班等方面的教学培训 会议。阿姆斯特朗博士的工作将集中在UMN兽医临床科学系，该系 她的四位导师中的三位都在。阿姆斯特朗博士的 K01 培训将为她启动独立项目做好充分准备 研究生涯的重点是改善受儿科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.