The research program of the McAlinden Lab is focused on understanding the molecular mechanisms regulating skeletal development with an emphasis on chondrogenesis. Of clinical relevance, the knowledge gained from these developmental studies will aid in designing strategies to improve tissue repair/regeneration. This is particularly beneficial in cases such as osteoarthritis where articular cartilage is severely degraded.
Ongoing projects in the laboratory involve transcriptional and post-transcriptional control mechanisms that regulate chondrocyte differentiation. We are utilizing sources of primary multipotent stem/stromal cells from human bone marrow aspirates and differentiating these cells in vitro toward the chondrocyte, osteoblast or adipocyte lineages. With respect to cartilage development, we are particularly interested in the distinct mechanisms that control the formation of articular cartilage and growth plate cartilage. Our goal is to attempt to recapitulate the process of articular chondrocyte differentiation in vitro and one strategy we are currently exploring is to manipulate transcription factor expression using lentiviral vector systems.
With respect to post-transcriptional regulation, we are interested in the role of precursor mRNA alternative splicing during development. For example, the type II collagen gene (COL2A1) is alternatively spliced during chondrogenesis and we have identified important cis elements and trans-acting factors that regulate this unique splicing event. In addition, we have recently identified two novel splice forms of COL2A1 that we intend to explore further. We are also in the process of generating a recombinant knock-in mouse model where COL2A1 alternative splicing will be disrupted; this will directly address the importance of this splicing event in skeletal development and the functional roles of the distinct isoforms in vivo. We anticipate future studies in the areas of cartilage disease models and tissue engineering by utilizing the knowledge we gain from our developmental studies.
Finally, we are involved in a clinical collaboration with Dr Martin Boyer, Associate Professor and Director of Hand Surgery Service in the Department of Orthopaedic Surgery at Washington University. This project will address if an immature tibial epiphyseal growth plate can be preserved for set periods of time ex vivo and subsequently survive and grow in vivo following microvascular allotransplantation. Research in my laboratory will facilitate in determining cell proiliferation, apoptosis and new synthesized bone in the epiphyseal plates after short-term transplantation periods.