PROJECT SUMMARY/ABSTRACT Ostechondritis dissecans (OCD) is a developmental orthopaedic disease affecting children and young adults. It is characterized by formation of osteochondral flaps or fragments within joints which causes pain and disability and predisposes to early onset osteoarthritis. Although recent studies demonstrated that discrete areas of epiphyseal cartilage necrosis (termed osteochondrosis), caused by focal failure of vascular supply, are the clinically silent precursor lesions of OCD, it is yet to be established how the extent of the inciting vascular failure, along with exposure to biomechanical trauma, determine whether these lesions heal or progress to clinically apparent disease. The overall objective of this proposal is to use porcine models to understand factors that influence the development, progression, and healing of OCD lesions. To achieve this objective, we will use two specific aims to test our central hypothesis that the extent of ischemic epiphyseal cartilage necrosis determines the development of OCD, and that lesion progression is influenced by biomechanical stress. Specifically, our aims have been designed (1) to investigate the relationship between the severity of vascular injury to the femoral trochlear epiphyseal cartilage and the formation and progression of OCD precursor lesions and (2) to determine the role that low vs. high impact biomechanical stress plays in the formation of subclinical osteochondrosis lesions and their progression to clinically apparent OCD. Our study will establish how the extent of vascular failure and exposure to biomechanical stress drive the clinical course of OCD and determine characteristic gene expression profiles across OCD lesion types. Conducting these studies in a large animal model will ensure timely translation of our results to inform clinical decision making in human patients, and will also help establish controlled exercise as a component of non- operative treatment. Importantly, these findings will also have applicability to other juvenile orthopaedic disorders of vascular origin such as Legg-Calvé-Perthes disease.