The Department of Orthopaedic Surgery at the University of Southern California can support two applicants interested in applying for this fellowship. The successful applicant will be involved in translational research program directed by Drs. Denis Evseenko and Joseph Liu, and Jay R. Lieberman, M.D. (Chair); a summary of the projects are provided below. Successful completion of this program will be a major plus for securing an Orthopaedic Surgery Residency position at USC. The fellow will have the opportunity to work on two novel projects.
Project abstractsProject I: Articular cartilage injury and lack of cartilage regeneration often predisposes patients to osteoarthritis. None of the current cell-based repair strategies generate long-lasting hyaline articular cartilage. Thus, focal critical size lesions of articular cartilage remain a major unmet clinical need. We propose a unique approach to cartilage regeneration based upon our recent findings and the development of an essential model to test this and subsequent therapeutic modalities. Based on our preliminary studies and existing literature we hypothesize that
controlled reactivation of the fetal program in adult chondrocytes by chemically defined small molecules will 1)
increase their regenerative potential by inducing a partial epigenetic and metabolic reprogramming and 2)
will delay accelerated aging induced by ex vivo expansion. We will develop a fully defined chemical approach to revitalize the cells to a fetal-like phenotype, with at least 100-fold expansion potential and assess the regenerative potential and stability of reprogrammed human primary articular chondrocytes delivered on an allogeneic collagen 1/3 scaffold in a Yucatan minipig model. We will use this model of focal cartilage injury for the structural, functional, and molecular assessment of cartilage regeneration. Overall, we propose that the reprogramming of adult articular cartilage cells will promote cell reversion to a juvenile, proliferative and anabolic cell state capable of generating new chondrocytes that repair the joint. Furthermore, we anticipate that the revitalization procedure will offer a transformative advantage in treating focal cartilage lesions. The long-term objective
is to develop a new therapeutic approach for articular cartilage restoration to improve the quality of regenerated cartilage and diminish functional limitations associated with cartilage injury. The current technology, if successful, will have a major impact on clinical practice and on the current care of cartilage lesions and subsequent prevention of OA. Project II: Approximately 5% of fractures do not heal. Traditionally, autogenous bone graft has been the gold standard for bone grafting procedures. Unfortunately, the supply of bone graft is limited and there is morbidity associated with the bone graft harvest. Recombinant bone morphogenetic protein (BMP) has been FDA approved for use in spine fusion and fresh tibial fractures. Unfortunately, supraphysiologic doses of BMP are needed to produce adequate bone formation. However, these large doses have been associated with complications and the clinical results are mixed. One potential solution to treat significant bone loss problems such as fracture non-union, revision total joint replacement and spinal fusion is regional gene therapy. Dr. Lieberman is a pioneer in this field and his lab is presently working on both autogenous and allogeneic strategies to enhance bone repair. Lentiviral gene therapy using genetically manipulated adipose derived stem cells that overexpress BMP-2 have been shown to heal critical sized bone defects. At the present time, the focus of the lab is to optimize these strategies for use in humans. The fellow will participate in a variety of
in vivo experiments that assess the efficacy of the transduced cells and carriers and be actively engaged in projects that have the potential to revolutionize the treatment of severe bone repair problems.
We are seeking two medical students who are in their 3rd or 4th year of medical school and are interested in pursuing a research year. If you are interested in applying, please send a cover letter, CV, medical school transcript, and Step II score report to [email protected]. 
