Project Summary 1 Fostering a diverse scientific workforce in the US is a key component of the NIH’s mission. As 2 such, PA-21-107 and NOT-NS-20-107 provide opportunities to supplement HEAL Initiative parent 3 awards with additional support of individuals from diverse backgrounds, as defined in PA-21-107. 4 This supplement application serves to offer additional training support related to this NIH mission 5 to parent award, UC2AR082196. This parent award is part of the RE-JOIN Consortium, which 6 seeks to define the sensory innervation of different articular and peri-articular tissues with a focus 7 on the knee and temporomandibular joint (TMJ). With an improved understanding of how different 8 neural subtypes are distributed through the joint and how these subtypes change with age and 9 disease, new therapies can be developed to reduce the heavy burden of chronic joint pain. In 10 particular, our team focuses on defining pathology-pain relationships between shifting joint 11 innervation patterns and the development of symptomatic OA. Our parent award achieves this 12 goal by investigating how innervation patterns change in rodent osteoarthritis (OA) models with 13 increasing age and OA severity, if pathology-pain relationships exist between joint innervation 14 and the presentation of symptoms in human OA patients, and whether neural ablation techniques 15 targeted at specific neural subsets can be used to selectively alter joint innervation and treat joint 16 pain. This supplement application compliments the parent award by offering a unique career 17 development opportunity related to the NIH’s mission for scientific workforce development, while 18 also identifying potential relationships between joint metabolism and shifting joint innervation 19 patterns. Because many metabolites are neuroactive and/or immunomodulatory, it is likely that 20 local alterations in joint metabolism (related to aging, obesity, and other co-morbid conditions) will 21 affect joint innervation and the presentation of OA pain and disability. For example, joint 22 metabolism is known to change with age through increased mitochondrial dysfunction and 23 oxidative stress, abnormal autophagy, and the metabolic reprogramming of macrophages. 24 Similarly, hypertension alters joint vasculature, which results in impaired perfusion, hypoxia, and 25 reduced nutrition supply to the joint. These local shifts in joint metabolism could explain links 26 between these comorbidities and OA progression, which could coalesce around shifting joint 27 innervation patterns and the development of chronic OA pain and disability. As such, the work 28 proposed in this supplement will leverage the parent UC2 award to address this gap in knowledge, 29 while synergistically providing a unique training opportunity related to NIH’s mission to develop a 30 diverse scientific workforce in the US.

Project Narrative Joint innervation is a complex network of different neural subtypes that vary with age, sex, and disease. Moreover, shifts in innervation likely relate to shifts in chronic joint pain. This supplement award to UC2AR082196 will allow for additional studies evaluating how joint innervation interacts with the immune system to drive chronic joint pain.