Research Highlights
Research is essential to the advancement of medicine. Members of the Department of Physiology are involved in a number of leading-edge biomedical research projects, all conducted with the ultimate goal of improving and advancing human health and welfare, and delivering the future of medicine, today.
Among the research projects currently under way in our laboratories:
Ilya Bezprozvanny
Dr. Bezprozvanny's research deals with the connection between calcium actions in nerves and neurodegenerative disease. Recent results show abnormal calcium handling by specific nerves in the brain may cause or contribute to neuronal dysfunction and cell death in Huntington's disease, spinocerebellar ataxias, and Alzheimer's disease. He is using genetic mouse models of these diseases to clarify the role of neuronal calcium signaling and to test potential therapeutic approaches.
Paul Blount
Dr. Blount's research is aimed at determining molecular, biochemical, and biophysical mechanisms underlying an organisms’ ability to detect mechanical forces. Such mechanosensation is necessary not only in our sense of touch, but in the ear for hearing and balance, as well as cardiovascular regulation. Because of its tractability and simplicity, he has primarily studied mechanosensitive channels in bacteria.
He has developed new genetic and mechanical methods for investigating how these molecules sense and respond to membrane tension brought about by forces. His work has also recently expanded to include investigating the potential use of these bacterial mechanosensors as potential drug targets, as well as developing them into ‘triggered nanovalves’ that could be used in drug-release devices, or “smart” contrasts, for MRI.
George DeMartino
Dr. DeMartino studies how proteins are degraded in cells by a unique ubiquitin-proteasome system. Intracellular protein degradation determines most basic cell functions by controlling the amounts of critical proteins, and becomes dysregulated in many human diseases including cancer, muscle-wasting diseases such as Muscular Dystrophy, and neurological diseases such as Parkinson's disease and Alzheimer's disease.
Based on our work, drugs against the proteasome are now used to treat cancers such as multiple myeloma.
Robin Hiesinger
Neurogenetics is the study of the genes that shape neuronal development and function. The genetic approach implies that it is indeed genes, their regulation and their products, that give rise to the complexity of neuronal networks. How can a few thousand genes and their regulatory elements contain the information required to wire a fly's brain to be capable of a feat like computing safe flight in three dimensions?
Dr. Hiesinger's work focuses on understanding the mechanisms that lead to the synaptic specificity underlying such accurate and reproducible wiring of neuronal networks.
Don Hilgemann
Dr. Hilgemann studies how transport proteins in membranes move ions (salts) that control electrical events for heart contraction and secretion by the kidney and pancreas. He developed a 'patch clamp' electrophysiological method to excise 'giant' membrane patches to study very fast changes (microsecond) in transport proteins.
This remarkable method is extended to study how two membranes fuse with each other to analyze what bring proteins into and out of a membrane. With these novel and sensitive techniques he is studying how different lipid molecules serve as signals to regulate the functions and positions of membrane proteins. These research projects are fundamental to understand numerous diseases that affect electrical signaling and secretion.
Youxing Jiang
Dr. Jiang studies how ion (salt) channel proteins control the flow of ions such as K+, Na+ or Ca2+ across the cell membrane and regulate many biological processes, such as the excitation of nerve and muscle cells, the secretion of hormones, and sensory transduction. There are two basic properties that define an ion channel: ion selectivity (what ions move through the channel) and gating (how fast ions move through the channel).
His study aims to decipher the molecular mechanisms of both selectivity and gating properties of channels using x-ray crystallography to visualize the atomic structure and relate this to a channel’s electrophysiological properties. Because of the prevalence and importance of ion channels in the human body, knowing their structures and functions helps understanding the underlying mechanisms of channel-related human pathologies.
Kris Kamm
Dr. Kamm is focused on defining signaling pathways that govern the contractile apparatus in smooth muscle tissues and cells. Excessive contraction of these cells underlies certain types of hypertension, coronary artery disease, and asthma. Current approaches are directed to elucidating roles of specific proteins in the contractile machinery and involve use of genetically modified mice expressing novel sensor molecules that allow imaging of cellular processes. Additional approaches involve turning gene expression off in adult mice as well as functional mutations in the genes of relevant proteins.
Smooth muscle cells undergo phenotypic modulation leading to cell migration and proliferation that contribute to the pathology of such diseases as aortic dissection, atherosclerosis, restenosis after coronary angioplasty, and pulmonary fibrosis. Elucidation of regulatory pathways involved in processes of cell motility will impact basic understanding and therapeutic approaches to these and other diseases.
Jen Liou
Something of a rock star in the world of calcium studies, Dr. Liou identified regulators of store-operated calcium signaling, where she found STIM1/2 as the long-sought calcium sensors in the endoplasmic reticulum (ER). The discovery sparked a renaissance in calcium research. STIM initiates signaling from the ER to the plasma membrane, where ORAI constitutes the calcium channel.
She continues to do research on calcium signaling using advanced live-cell imaging techniques and two state-of-the-art microscopes that she has built since joining UT Southwestern. She plans to extend her studies to investigate calcium signaling in immune responses which may lead to a drug that targets STIM or ORAI, and immunological disorders.
Yi Liu
Dr. Liu studies how daily biological clocks function. The importance of biological clocks in human physiology and mental health is evident from their ubiquitous influence on a wide range of cellular and organismal processes, including sleep/wake and body temperature cycles, endocrine functions, drug tolerance and resistance, and the phenomenon of jet lag. He uses a combination of molecular, biochemical, genetic, and physiological approaches to understand how cells generate the daily rhythmicity, how it is regulated by the environment, and how it controls diverse physiological activities.
Ryan Potts
His research is focused on understanding the basic molecular, genetic, and cellular events that give rise to cancer. His lab is currently studying a family of proteins, called MAGEs. These proteins have the peculiar property that they are normally only located in the testis, but are aberrantly found in a wide-variety of cancer types, including brain, breast, colon, lung, and skin. Importantly, the presence of these proteins in tumors correlates with poor survival of cancer patients. However, the function of MAGE proteins in cancer cells has been mysterious. His lab is tackling this challenge with biochemical and cellular studies to discover the enigmatic function of these proteins in cancer. This work will help our understanding of how normal cells become cancerous and open the door to new tumor-specific therapeutic targets.
Joyce Repa
Dr. Repa studies the role of orphan receptors that function in the nucleus of a cell to affect lipid and carbohydrate metabolism. The retinoid X receptors (RXRs) and liver X receptors (LXRs) regulate cholesterol absorption and have an impact on the development of atherosclerosis. In another project, the LXRs alter insulin secretion from islets of the endocrine pancreas, thus playing a potential role in the development and/or therapy of type 2 diabetes.
James Stull
Dr. Stull, Department Chair, studies genetic approaches to understand how the smooth muscle cells in blood vessels contract, and what goes wrong when they contract too much, causing an increase in blood pressure. His lab has identified a key enzyme related to the enzymes found in the heart that acts on the molecular motor myosin. Also, his investigations of the two heart enzymes that act on myosin, and thereby affect the pumping ability of the heart, may provide perspectives on novel clinical strategies to manage heart failure.
Phil Thomas
Dr. Thomas studies the fundamental processes by which proteins fold into functional structures. Understanding how the sequence of a protein directs the formation of a specific three-dimensional structure remains one of the great unmet challenges of modern biology. His work established that aberrations in the folding process underlie many diseases. In the past year, unexpected mechanisms by which the protein machinery in the cell senses the process have been uncovered.
Jiang Wu
Dr. Wu's research is focused on how chromatin states and chromatin remodelers regulate gene expression in response to signals during stem cell differentiation, tissue development, and tumorigenesis. Using the mammalian developing brain as a model system, she combines molecular biology, biochemistry, and genetic approaches to investigate the molecular mechanisms of chromatin regulation of signaling pathways. She discovered dual roles of a chromatin remodeling complex in regulating Sonic hedgehog (Shh) signaling pathway, which is essential for neural differentiation, as well as stem cell proliferation. The study provides another level of regulation and potential therapeutic targets for Shh-related birth defects and cancer.
Helen Yin
Dr. Yin studies how a membrane lipid, PIP2, regulates essential membrane functions that are critical to conveying signals for cell growth and response to cell injury. Derangement of these PIP2-regulated membrane functions leads to inappropriate cell growth, intracellular signaling, and response to oxidative injury. Her studies have relevance for cancer development, neuronal regeneration, and response to inflammatory injury associated with burn.
Alec Zhang
Dr. Zhang's long-term goal is to gain a comprehensive understanding of the molecular mechanisms that govern the adult stem cell fate determination of adult stem cells and cancer stem cells, and to apply the knowledge obtained from these studies to the development of new stem cell transplantation strategies and gene therapies for treating cancer and other diseases. His studies are focused on blood stem cells and leukemia stem cells.