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 underway in our laboratories:
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. Bezprozvanny Lab
Dr. Blount’s research is aimed at determining molecular, biochemical, and biophysical mechanisms underlying an organism’s 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. Blount Lab
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. DeMartino Lab
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 brings 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. Hilgemann Lab
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. Jiang Lab
Dr. Kamm is focused on defining signaling pathways that govern the contractile apparatus in smooth muscle tissues and cells. Onset of smooth muscle contraction comes about through a calcium-dependent phosphorylation of the motor protein myosin by myosin light chain kinase. Phosphorylated myosin interacts with actin to develop force. Relaxation results from myosin dephosphorylation by a type 1 phosphatase. Recent findings that mutations in smooth muscle isoforms of myosin, actin, and myosin light chain kinase are linked to familial forms of thoracic aortic aneurysms and dissections (TAAD) suggest that derangements in contractility may underlie or contribute to the disease.
Currently, in collaboration with Dianna Milewicz, the lab is investigating contractile and signaling properties of aortas from mice expressing TAAD variants of these smooth muscle contractile proteins. Biochemical, biophysical, cell biological, and physiological tools are used to dissect mechanisms that may lead to pathology. Kamm Stull Lab
Dr. Liou’s research aims to elucidate molecular mechanisms of cell signaling involving inter-organelle communication. Her laboratory has pioneered synthetic-biology, chemical-genetics and live-cell imaging techniques to study the functions and regulation of nanosized inter-organelle membrane contact sites. Inter-organelle communication is important for cell homeostasis and responses to stimulation. Many diseases have been associated with defective inter-organelle communication including severe combined immunodeficiency, muscular disorders, and cancer. Dr. Liou’s research has had strong impact on biomedical research and holds promise for therapeutic applications.
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. Liu Lab
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.
Dr. Stull studies signal transduction mechanisms related to smooth muscle disease and the phosphorylation of the motor protein myosin. Myosin activity is enhanced for tracking on actin thin filaments by the calcium-dependent myosin light chain kinase which phosphorylates a regulatory light chain subunit of myosin while myosin light chain phosphatase dephosphorylates the light chain. Impaired light chain phosphorylation causes failed smooth muscle functions involving the hollow organs of the body (blood vessels, airways, intestines, and bladder). The phosphorylation of myosin is not controlled by a simple cascade, but discrete signaling modules forming cellular networks with different second messenger systems.
He has established that all smooth muscles of the body require myosin phosphorylation by a smooth muscle specific myosin light chain kinase. This phosphorylation is necessary for control of blood pressure by smooth muscle cells in blood vessels, movement of digested food in the stomach and intestines, maintenance of airways in the lungs and emptying of the urinary bladder. He has investigated interconnected biochemical networks that affect myosin phosphorylation using genetically modified mice using biophysical, biochemical and physiological approaches. Primary hypotheses are directed to identifying the key signaling proteins essential for smooth muscle contraction that may contribute to the development of different smooth muscle based diseases, including aortic aneurysm and dissection in humans.
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. Thomas Lab
Dr. Wu’s research focuses 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 the current genomic and proteomic techniques, as well as the classic molecular biology, biochemistry, and genetic approaches to investigate the epigenetic mechanisms regulating transcription outcomes of signaling pathways. Her study provides another level of regulation and potential therapeutic targets for a number of developmental brain diseases such as autism and pediatric medulloblastoma. Wu Lab
Dr. Yin studies how the membrane lipids, PI4P and PIP2, regulate essential membrane functions that are critical to conveying signals for cell growth, cytoskeletal regulation, and response to cell injury. Derangement of these PI4P- and PIP2-regulated membrane functions leads to inappropriate cell growth, intracellular signaling, cytoskeletal remodeling, response to oxidative injury, and autophagy. Her studies have relevance for cancer development, neuronal regeneration, and responses to inflammatory injuries. Yin Lab
Dr. Zhang is interested in cell-surface receptors, how the extrinsic cues regulate the cell fates of adult stem cells and cancer stem cells, and applying the knowledge obtained from these studies to the development of novel cell, gene, and immune therapies for treating cancer and other diseases. His studies are focused on blood stem cells and leukemia stem cells, and the interplay among stem cells, cancer, and immunity. Zhang Lab