Thomas L Pannabecker

Research Interests

The overall goal of my research is to advance our understanding of the relationships between structural organization and function, including epithelial transport of inorganic ions, urea, and water in nephrons and blood vessels of the mammalian renal cortex and medulla. This functionality is particularly important in understanding the urine concentrating mechanism (UCM), sodium and water balance, and the long-term control of arterial pressure. In recent years we’ve been thinking about the relationships of our work to cardiovascular disease and kidney injury and our research has grown to include investigation of functional architecture of human kidney. The three-dimensional architecture of medullary loops of Henle, vasa recta and collecting ducts, and axial heterogeneity of solute and fluid permeabilities along these structures play critical roles for integrated regulation of water, urea, and ion movements; these structure/function relationships underlie axial and lateral compartmentation and lead to formation of multiple recycling and countercurrent systems that generate and sustain the corticomedullary osmotic gradient and the UCM. Our recent studies have suggested new ideas about fluid and solute exchanges between tubule and vessel segments and the many compartments formed by them in rodent and human kidneys, identified novel membrane transporters for urea in the renal medulla and developed techniques for investigating tubular segments never before studied in isolated in vitro preparations. Our structural and functional studies have already identified several previously unknown inner medullary tubular, vascular, and interstitial compartments that may be of paramount significance in the UCM and overall medullary function (Pannabecker, 2008; Pannabecker et al., 2004; Pannabecker and Dantzler, 2004; Pannabecker and Dantzler, 2006; Pannabecker and Dantzler, 2007; Pannabecker et al., 2008b; Wei et al., 2015). The “passive mechanism” is the most widely cited explanation for generation of the inner medullary osmotic gradient. On the basis of our new ideas about inner medullary fluid and solute exchanges we have begun to develop with Drs. Harold and Anita Layton of Duke University several passive models, such as our “pipe mode” and “solute secretion” models (Layton et al., 2004). New insights into inner medullary three-dimensional nephron architecture have brought new meaning to these models (Layton et al., 2009; Pannabecker et al., 2008a). Our recent studies on the architecture of inner medullary vasculature (Kim and Pannabecker, 2010; Yuan and Pannabecker, 2010) and functional studies of inner medullary capillaries (Evans et al., 2015) should provide a foundation for future UCM models that incorporate redistribution of fluid and solutes by way of bloodflow. Inclusion of capillary networks will bring new dimensions to future models of the concentrating mechanism that are presently being developed by my collaborator Dr. Anita Layton. We presently investigate inner medullary architecture using static images obtained from fixed kidney, in association with immunohistochemistry. From these we build three-dimensional models to investigate nephron and vessel architecture and expression of proteins associated with fluid and solute transport. We investigate fluid and solute permeability in isolated, perfused tubules. However, improved systems approaches to investigating tubular and vascular function in the living kidney are essential to understanding the multiple axial and lateral compartments of the inner medulla and to understand how they are integrated in dynamic fashion. Intravital microscopy is one approach we anticipate may be useful for carrying out quantitative analyses of fluid and solute movements within and across the multiple inner medullary compartments. This work is currently funded as a multiple principle investigator grant from the National Science Foundation with Dr. Anita Layton (Collaborative Research: Comparative Study of Desert and Non-Desert Rodent Kidneys). From these studies we anticipate obtaining essential information for constructing improved models of the UCM. We are presently developing intravital microscopy techniques in collaboration with faculty of Indiana University Medical Center at the Indiana Center for Biological Microscopy. This Center has a national reputation and well-funded endowment for conducting intravital microscopy of the kidney. Our current work also continues with an R01 grant from the National Institutes of Health with me as Principal Investigator (Integrated Tubular and Vascular Structure and Function in Renal Inner Medulla). For nearly eight years we have been developing a new renal model of the UCM, a project funded to me by two National Science Foundation grants as well as with further support from fellowships to several undergraduate students. The kangaroo rat is a desert rodent that rarely drinks fluids and produces highly concentrated urine. We hypothesize that structural and functional features important for the UCM are exemplified in the kangaroo rat kidney, and that parallel studies with the Munich-Wistar rat will make those features more readily recognizable. Prior to initiating studies on the UCM, I was deeply involved with studies of fluid and electrolyte transport and their regulation in invertebrate renal tubules (the Malpighian tubule). Invertebrate models are increasingly recognized for their potential as an alternative to mammalian intact organ models, and have already provided powerful insights into vertebrate renal function, building on a rich history as models for growth and development. Another major proposal (NIH-NIAID vector biology study section; submitted October 2016), for which I am Co-PI, is a collaboration with Drs. Andrew Nuss, an assistant professor in the Dept. of Agriculture, Nutrition and Veterinary Sciences and David Schooley, a professor in the Dept. of Biochemistry, both at the University of Nevada-Reno. This project will enable us to begin developing insect renal models of guanylate cyclase receptors and their ligands and physiology. My research has been brought to the attention of national and international audiences through invited speaking engagements at national and international conferences and at public and private research institutions and universities within the United States. Our original research on the UCM has been published primarily in the American Journal of Physiology – Renal Physiology, one of the leading international publications for the field of renal physiology, and has been the topic of several invited review articles in the past four years (Donald and Pannabecker, 2015; Pannabecker and Layton, 2014; Pannabecker, 2012; Pannabecker, 2013; Pannabecker, 2015a; Pannabecker, 2015b). Fulfillment of academic goals of service and outreach are accomplished in several ways, but chiefly through graduate student and postdoctoral training, journal reviews, participation in organizing the Arizona Physiological Society Annual Meeting as Secretary-Treasurer and other AzPS executive committee responsibilities, organizing conference symposia that focus on keeping cutting-edge advances in the field of renal salt and water homeostasis at the forefront and participation in NSF and other grant review committees and APS organizational committees. A close encounter with basic research is increasingly viewed as a necessary or highly desirable component of university experience by our undergraduate physiology students. Since university committee work and classroom teaching are currently not considered part of my workload, I have chosen to reach out to students by making myself and our research facilities available to many of these individuals. I also provide laboratory research experiences for Tucson area high school physiology teachers through programs funded by the National Science Foundation and The American Physiological Society in addition to my NSF and NIH grants, and these provide financial support to these individuals during the summer months as well as travel funds for attending the national meeting of The American Physiological Society. Student motivations are diverse, but at least a few students have a keen desire to make a significant impact on basic research outcomes. These few can indeed impact fundamental research; their work is generally buttressed by prior or subsequent contributions from other students.