PROJECT SUMMARY. Candidate: Dr. Zellers is a physical therapist (Doctor of Physical Therapy, Columbia University) with a PhD in Biomechanics and Movement Science (University of Delaware). She is Assistant Professor in Physical Therapy and Orthopaedic Surgery at Washington University School of Medicine in St. Louis, having completed her postdoctoral fellowship (Washington University School of Medicine). Dr. Zellers is a translational, tendon researcher with expertise in in vivo and ex vivo assessment of human subjects and tissues to elucidate person- and tendon-specific characteristics influencing patient treatment and outcomes. Mentor and Advisory Committee: Dr. Farshid Guilak will be primary mentor, bringing extensive experience as a principal investigator in orthopaedics and specific expertise in leveraging the mouse models included in this study to answer similar questions regarding the effect of obesity in the context of osteoarthritis. Drs. Alayna Loiselle and Spencer Lake are co-mentors imparting tendon-specific expertise including mechanical, histological, and molecular biological outcomes assessment. Drs. Gretchen Meyer and Simon Tang are co- mentors with experience leveraging similar animal models to investigate questions relating to fat-muscle crosstalk and collagenous soft tissue healing, respectively. Training Plan: In this Career Development Award, Dr. Zellers will gain training and experience in leveraging animal models (murine models of obesity, lipodystrophy, and tendon injury) to investigate mechanisms underlying observations gleaned from her clinical, human studies research line. The proposed training plan emphasizes building skills in incorporating animal models into her translational research program. Training goals also incorporate biological approaches to tendon assessment, specifically histological and molecular biological techniques, which will carry over to Dr. Zellers’s study of human tendon tissue. This award would provide the training and experience for Dr. Zellers to grow as a translational researcher with a comprehensive toolkit of in vivo and ex vivo techniques spanning preclinical models to human tissues to human subjects. Research: Obesity presents both mechanical and biochemical effects on tendon tissue homeostasis and healing that have not been well elucidated. The proposed study leverages murine models of obesity and lipodystrophy to determine the effects of high bodyweight and metabolic dysfunction on tendon tissue. We hypothesize that metabolic dysfunction, more so than mechanical load, promotes tendon degeneration (Aim 1) and impairs healing (Aim 2), evidenced by abnormal histological appearance, altered gene transcription, disrupted collagen organization, and impaired tendon function at the tissue and functional performance levels. Institutional Commitment to the Candidate: Dr. Zellers holds a tenure-track faculty position and has been provided bench and clinical laboratory space, start-up package, and trai...