News

Congratulations to Amanda Wahl, graduate student in the CMPP program, laboratory of Dr. David Yule. Amanda was recently awarded a three-year NIH F31 Ruth L. Kirschstein Predoctoral Individual National Research Service Award entitled, "Elucidating the mechanisms of salivary gland dysfunction following gamma-irradiation utilizing an experimental and computational approach".

Project Summary:

Individuals diagnosed with head and neck cancer undergo radiation therapy as a standard treatment. However, in the process of using radiation therapy to shrink the tumor, the salivary glands are inadvertently and irreversibly damaged. This damage manifests as a loss of saliva secretion, occurs rapidly without marked cell death, and leads to deleterious effects, including loss of taste, oral infections, and xerostomia (dry mouth). The mechanism by which this early loss of function occurs, is currently unknown and presently there is little in the form of

treatment, with most options being palliative. Thus, there is a pressing need to expand our understanding of salivary gland physiology and the effects of g-irradiation on both the structure and function of the salivary gland. This proposal utilizes experimental techniques including confocal, Stimulated Emission Depletion (STED) and intravital microscopy. Each technique will be employed for use in a variety of assays to investigate the structural and functional consequences of acute g-irradiation on salivary glands. This in vitro and in vivo experimental

approach will additionally be used in combination with computational modeling through a long-term collaboration to understand in detail the effect of g-irradiation on secretion. In an iterative manner, experimental data will be input to the computation model and subsequently used to make further predictions which will be experimentally tested- furthering our understanding of physiology and pathology of salivary glands. In these studies, this experimental-computational approach will be used to determine how alterations within the salivary gland impact

its function, leading to dry mouth, and an eventual permanent loss of glandular tissue and function. This proposal addresses three different mechanisms that may dictate this loss of function. These include an alteration in functioning of gap and tight junctions, calcium signaling, and mitochondrial bioenergetics. By examining each of these aspects, the experimental data can be integrated into the computational model. The great utility of this approach is that many iterations of computational experiments can be completed in parallel with these in vitro

and in vivo studies and used to suggest further experiments and make predictions. The dynamic utilization of this computational-experimental approach will facilitate understanding how an alteration in a component of the gland's secretory machinery following g-irradiation might alter saliva production. Ultimately, this approach is designed to forecast potential novel therapeutic approaches for treating g-irradiation induced salivary dysfunction.

Congratulations to Lara Terry, who has just had a paper accepted in JBC. Based on this paper she was asked to present a seminar at the European Calcium Society General Assembly plenary session in honor of the memory of Mike Berridge.

The inositol 1,4,5-trisphosphate receptor IP3R is a ubiquitous intracellular Ca2+ release channel which plays fundamental roles in a diverse array of physiological responses. More recently, an ever-increasing number of mutations in the protein have has been reported to be associated with a range of human disease including spinocerebellar ataxia, Gillespie syndrome, peripheral neuropathies and anhidrosis. Lara Terry's thesis project has focused on investigating the mechanisms which underlie alterations of channel function of these mutations. Recently some of her work "Disease associated mutations in Inositol 1,4,5-trisphosphate receptor impair channel function" was accepted for publication in the Journal of Biological Chemistry.

An exciting consequence of the publication is that Lara has been invited to speak at the European Calcium Society "Frontiers in Calcium Signaling" mini symposium in honor of the memory of Sir Michael Berridge, who passed away earlier this year. As many of you know, Mike Berridge is a towering figure in the calcium signaling field having been pivotal in the discovery of IP3 as a second messenger, together with first demonstrating its role to release Ca2+ from intracellular stores. Notably, Lara is one of only six speakers presenting at the meeting, the others being past students of Mike's. Please join us in congratulating Lara on this recognition of her excellent work.

Sarah R. Heilbronner, PhD, will receive the Postdoctoral Achievement Award at the 2016 Convocation, on September 8. She is currently a postdoc in Dr. Suzanne Haber's lab, where she is studying the neural circuitry associated with reward processing, decision-making, and executive function.

Along with the other members of Dr. Haber's team, Sarah is working to determine the anatomical connections that are affected by neurosurgical interventions for psychiatric disorders (such as deep brain stimulation).

Professor David I. Yule, Ph.D., will also receive the Faculty Teaching Award, specifically the Trainee Academic Mentoring Award in Basic Science, as well as the Louis C. Lasagna Endowed Professorship at convocation. The Yule Lab studies intracellular calcium signaling in cells which are typically, electrically non-excitable. In cells such as the liver, exocrine, pancreas, salivary glands and various cells in the blood, increases in intracellular calcium are fundamentally important for diverse processes including secretion of digestive enzymes and fluid, glucose metabolism together with cellular growth and differentiation.

Congrats Sarah and David!

David Yule

David Yule, professor of pharmacology and physiology, has been appointed the Louis C. Lasagna Professor in Experimental Therapeutics for five years, effective July 1. He retains his joint appointments as professor of medicine and as professor in the Center for Oral Biology.

For the past 15 years, Yule has studied calcium’s role in disorders in which calcium signaling and secretions are disrupted, such as Sjögren’s syndrome—in which patients experience dry mouth due to a lack of saliva—and acute pancreatitis.

Using state-of-the art imaging and electrophysiological techniques, Yule’s lab monitors calcium signals to achieve a better understanding of the mechanisms that underlie these signals with the goal that the studies will give insight into the control of important physiological processes in both normal physiology and disease states.

• Learn more about Yule’s research and lab

Yule received his PhD in physiology from the University of Liverpool in the United Kingdom. His research has been published in numerous journals, including the Journal of Biological Chemistry, Proceedings of the National Academy of Sciences, Science Signaling, and the Journal of Physiology. Yule serves on the editorial board for Gastroenterology, the preeminent journal in the field of gastrointestinal disease.

The Lasagna professorship honors Louis Lasagna, who served as chair of the Department for Pharmacology from 1970 to 1983, and brought the department to national recognition as a center of training and research. Lasagna, who was known for pioneering the study of placebos and writing an alternative Hippocratic oath, died in 2003.

The salivary gland secretes saliva that helps us chew and swallow the food we eat. The pancreas secretes digestive juices that enable our bodies to break down the fat, protein, and carbohydrates in the food. Secretions like these are important in countless activities that keep our bodies running day and night. A study published today in the journal Science Signaling uncovers a previously mysterious process that makes these secretions possible.

At the heart of the new study is calcium, which is present in all of our cells and is a gatekeeper of sorts: an increase in calcium in our cells opens up “gates” or “channels” that are required for the production and secretion of fluids like saliva. If calcium doesn’t increase inside cells the gates won’t open, a problem that occurs in diseases like Sjögren’s syndrome. Sjögren’s patients experience dry mouth due to a lack of saliva and have difficulty chewing, swallowing, and speaking, which severely hampers quality of life.

For the past 15 years David I. Yule, Ph.D., professor in the department of Pharmacology and Physiology at the University of Rochester School of Medicine and Dentistry has studied calcium’s role in Sjögren’s and other disorders in which calcium and secretions are disrupted, like acute pancreatitis. In the new study he answers an important question that has stumped scientists for years: what does it take for a particularly important calcium channel to open and start these processes?