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Atum Buo

 

Molecular Medicine

Area of Doctoral Study: Orthopaedics; Molecular Medicine Cell Physiology and Pharmacology

Undergraduate Institute: Haverford College

Research Advisor: Joseph Stains, Ph.D.

Description of Research

My research focuses on the gap junction protein connexin 43 and elucidating the connexin 43-associated signaling pathways that regulate osteoblast differentiation and function. Diseases of low bone mass such as osteoporosis profoundly impact society and threaten the livelihood of future generations. Current therapies for the restoration of homeostatic bone remodeling are limited and focus primarily on the attenuation of osteoclast activity. As such, efforts have turned toward understanding the role of gap junction signaling in bone as a potential means of enhancing the anabolic function of bone-building osteoblasts. Connexin 43, the most predominantly expressed gap junction protein in bone, permits cell-to-cell communication of signals between bone cells that regulate osteoblast and osteocyte function and ultimately impact bone metabolism. Despite the clear importance of the role of connexin 43 in skeletal tissue, the underlying molecular details enabling connexin 43 to regulate osteoblast differentiation and bone mass accumulation are largely unclear. Any therapeutic strategy that implements connexin 43-based signaling in hopes of enhancing bone formation would require a comprehensive understanding of the molecular details underlying the ability of connexin 43 to impact skeletal metabolism. I hypothesize that connexin 43 regulates osteogenesis via the activation of signaling cascades that converge upon the master transcriptional regulator of osteogenesis known as Runx2. To address this, my approach involves the implementation of standard biomolecular techniques, primary cell models, and an innovative animal breeding strategy, all of which will help determine in connexin 43 and Runx2 functionally intersect. Convergence of connexin 43-dependent signaling on the essential activity of Runx2 would explain how connexin 43 is able to regulate the expression of the wide range of osteoblast genes responsible for osteogenesis. Confirmation of this mechanism of action will hopefully resolve prevalent knowledge gaps regarding how connexin 43 impacts osteoblast and osteocyte function, with the long-term goal of applying the knowledge gleaned from these studies to the development of therapeutic strategies that promote bone formation.