Paul Alexander Welling, M.D.

Awards and Honors

Degrees:

M.D., University of Kansas School of Medicine (Kansas) (1988)

B.S., University of Kansas (Kansas) (1983)

Research Interests

Molecular Mechanisms of Salt Balance, Hypertension, and Kidney Disease

Daniel Raben Ph. D.

Research Interests

Biochemistry and chemistry of lipids and lipid metabolizing enzymes involved in signaling cascades

A major effort in our laboratory is focused on understanding the biochemistry and chemistry underlying the molecular aspects involved in regulating lipid metabolizing signaling enzymes and the physiological roles of this regulation. Control of lipid metabolizing enzymes involves the modulation of two key parameters; their sub-cellular distribution and their intrinsic enzymatic activity. Our studies have concentrated on three families of lipid-metabolizing signaling enzymes: diacylglycerol kinases, phospholipases D, and phospholipases C.

Specific Areas of Interest

Interfacial Enzymology of Lipid Metabolizing Signaling Enzymes: We are particularly interested in identifying the critical modulating proteins, lipids, and post-translational modifications that alter the localization and/or activity of lipid metabolizing enzymes.  In these studies we consider the fact that these enzymes act as interfacial enzymes and their regulation includes a number of interfacial-dependent parameters.  Our recent studies have identified some of the diacylglycerol metabolizing enzyme DGK-θ (diacylglycerol kinase-theta) interfacial parameters that are altered upon neuronal depolarization.  Further, our studies demonstrated that activation of DGK-θ requires a protein that contains a polybasic region.  We have recently obtained evidence that identifies at least one, if not only, activator binding domain on DGK-θ.

Enzyme Structure/Function Studies: We are also interested in the structural components of these enzymes that are critical for their distribution/re-distribution to specific sub-cellular compartments.  Additionally, and to compliment the enzymology studies, we are interested in elucidating the catalytic mechanism(s) of these enzymes.  These studies will be conducted partly in collaboration with Dr. Mario Amzel.  Our long-term goal is to understand the biochemistry and chemistry of these enzymes and determine how changes in their sub-cellular localization and/or enzymatic activity affect their signaling functions.

Physiological Functions of DGKs in Neurons: There is growing evidence that DGKs play physiological roles in mammalian neurons. This evidence includes cellular localization of specific isoforms, and the observations that likely modulate (a) susceptibility to epileptic seizures (DGK-ε), (b) neuronal spine density (DGK-ζ and DGK-β), and (c) pre-synaptic glutamate release during DHPG (3,5-dihydroxyphenylglycine)-induced long-term potentiation (DGK-ι).  We are currently examining the role of DGK-θ in glutamatergic neurons.  These studies have initially focused on identifying the physiologic regulator of DGK-θ, and test the hypothesis that this enzyme modulates induced glutamate release in these mammalian neurons.  We discovered that DGK-θ modulates glutamate release from cortical and hippocampal neurons in part by modulating synaptic vesicle cycling.  These studies are conducted in collaboration with Dr. Rick Huganier’s laboratory.

Mark Donowitz MD

Research Interests

Mark Donowitz, M.D., has had a distinguished career of scientific discovery, mentorship of young researchers and advocacy for the gastroenterology specialty. Dr. Donowitz is LeBoff Professor of Medicine and Professor of Physiology, Director of the Hopkins Center for Epithelial Disorders at The Johns Hopkins University School of Medicine, and is Founding Director of the NIH/NIDDK Hopkins Conte Digestive Diseases Center for Basic and Translational Research. He was President of the American Gastroenterological Association 2006-2007. He also served as President of the Gastroenterology-Research Group. He has received the Distinguished Achievement Award and as well as the Davenport Memorial Prize from the American Physiology Society, and the Distinguished Achievement in Basic Science Award from the American Gastroenterological Association, and is a Fellow of the American Association for the Advancement of Science. His scientific focus has been to understand regulation of intestinal Na absorption in normal digestive physiology and abnormalities that contribute to diarrheal diseases. His group was the first to recognize the mammalian Na/H exchanger gene family, to clone the epithelial isoforms, and to trace the evolutionary development of the gene family. He has examined structure/function aspects of the exchangers and identified the large, multiprotein complexes in which the epithelial NHEs function. In addition, his group identified a gene family of PDZ containing brush border proteins called the NHERF family which are scaffolding proteins which interact with NHE3 and are involved in forming the multiprotein complexes, are critical for its regulation, and take part in its association with the cytoskeleton. He has pioneered use of human mini-intestines made from normal human subjects to advance understanding of human digestive physiology and pathophysiology especially related to host-pathogen interactions.

Publications

Bibliography

Valina Dawson Ph. D.

Research Interests

Dr. Dawson’s laboratory is actively engaged in discovering and defining cell signaling pathways that lead to either neuronal survival or neuronal death. The lab has named a new cell death process Parthanatos. In the brain, Parthanatos is important in ischemic and excitotoxic injury and in models of Parkinson’s disease. The cell death mechanism involves nuclear activation of poly(ADP-ribose) polymerase and mitochondrial release of apoptosis inducing factor in the integration of the death signal; current research aims to further understand how this pathway works. She has characterized neuronal injury and survival pathways in cell, fly and mouse models of Parkinson’s disease and stroke. She is focused on several monogenic forms of Parkinson’s disease including parkin and LRRK2, as well as the new sporadic model of Parkinson’s disease using pre-formed fibrils of alpha synulcein in order to begin to define the biochemical signaling important to Parkinson’s disease. Yeast, cellular, fly and mouse models along with human neuronal cultures and human postmortem tissue explore survival and disease signaling events relevant to Parkinson’s disease. . In addition to cell death, the team also strives to understand how cells survive by characterizing survival genes and proteins involved in preconditioning. The Dawson laboratory employs advanced technologies in high throughput screening, next generation sequencing including RNA Seq and ChIP Seq, ribosomal foot printing, and high throughput proteomic analysis coupled with advanced computational biology to investigate signaling networks important in stroke, Parkinson’s disease and other neurodegenerative disorders. The overarching goal of the research is to understand death and survival signaling in order to identify new targets for therapeutic development.

Publications

Bibliography