Regenerative and Aging Biology
Ph.D., University of Utah, Genetics, 2005
B.S., Bates College, Biology, 1996
My research centers on identifying and understanding the genetic circuitry that defines organ regeneration, with a particular focus on miRNAs. Organ regeneration has captivated the fascination of scientists and the general public for well over 300 years, yet to date we know very little about the genetics that stimulate the process. A striking aspect of organ regeneration is how injury transforms differentiated, functional tissue into proliferative, regenerative cells that coordinate tissue replacement. Such spectacular biological changes necessitate dramatic modulation in developmental genetic programs. During my research on appendage and cardiac muscle regeneration, I have discovered that microRNAs (miRNAs) play a central role in this process. These robust regulators of genetic programs comprise a novel class of small, noncoding RNAs that regulate gene expression by repressing protein translation.
Recently, the zebrafish has emerged as a powerful vertebrate genetic model organism for studies in organ regeneration due to ease of genetic manipulation and enhanced regenerative capacity. Notably, the zebrafish appendages, retina, central nervous system, and heart are capable of robust regeneration. My laboratory uses the zebrafish to elucidate the genetic circuitry that controls regeneration of two organ systems in response to injury: the adult heart and the caudal fin appendage. The zebrafish heart robustly regenerates missing or damaged cardiac tissue following a partial ventricular resection procedure in as little as 30-60 days. Equally impressive is the ability of a caudal fin to regenerate bone, nerves, blood vessels, epidermal, and pigment cells in about 7-10 days following complete amputation. How is this remarkable process controlled at the genetic level? We are taking a multi-faceted approach to understanding the contributions of miRNAs during the initiation and propagation of the regenerative cascade.
I. What factors control cardiomyocyte proliferation during myocardial regeneration?
A key difference between mammals and zebrafish is the response to cardiac trauma. The injured mammalian heart replaces necrotic myocardium with collagen-laden scar tissue. In contrast, in response to injury, the zebrafish heart quickly seals the wound with a fibrin clot, followed by cardiomyocyte proliferation and neovascularization of the new myocardium. However, we know very little about the genetic pathways that initiate, promote and complete this process. One project will be to interrogate the roles of candidate miRNAs, identified from profiling experiments, to elucidate roles during heart regeneration.
II. Understanding positional memory during appendage regenerative outgrowth
During appendage regeneration in urodeles and teleosts, tissue replacement is meticulously regulated such that only the appropriate structures are recovered, a phenomenon referred to as positional memory. How cellular position is translated into regeneration and proper patterning of only missing or damaged tissue has perplexed the regeneration community since the 1600s. We will use the caudal fin to identify and characterize miRNAs that are expressed in a proximodistal gradient. These candidate factors will aid in our understanding of how regenerate size is controlled and how proper patterning of the regenerate is regulated.