My research interest is the control of neuronal gene expression. The major focus of the lab is on the neuropeptide CGRP and its role in migraine. The role of CGRP in migraine is supported by the ability of CGRP to cause headache and the recent efficacy of a CGRP antagonist as an antimigraine drug. We have found that the CGRP gene is up-regulated by cytokine-induced MAP kinases and repressed by antimigraine drugs that appear to act via an unusually prolonged calcium signal. We are currently investigating these mechanisms using adenoviral-mediated gene transfer to cultured trigeminal neurons and intact ganglia in vivo. We are also using gene transfer and transgenic mice to regulate CGRP receptor activity in the vasculature and nervous system by overexpressing the RAMP1 subunit of the CGRP receptor. The RAMP1 transgenic mice are sensitized to CGRP-induced neurogenic inflammation. The RAMP1 transgenic mice display a unique phenotype has raised the possibility that these mice may provide a model for some aspects of migraine, which is currently being explored. In collaborative projects, we are studying the beneficial effects of CGRP against hypertension and following myocardial infarction in the RAMP1 mice. Other collaborative projects include the regulation of serotonin biosynthesis, which may be important in migraine and behavioral disorders, and use of the CGRP promoter to target a dominant negative oncogene to specific neuroendocrine cells. The overall goal of these projects is to develop effective diagnostic and therapeutic strategies.
Our laboratory is interested in how proteins are degraded in lysosomes. This is a fundamental process of all eukaryotic cells necessary for regulating a variety of cell surface proteins. This process is often termed “downregulation”, and is a central feature of virtually all physiological processes that rely on cell surface membrane proteins. Failure to properly downregulate particular proteins can lead to or exacerbate a variety of pathophysiological conditions such as cancer, hypertension, and cardiac disease.. Our overall goal is to understand the protein machinery common in all cell types that controls the delivery of membrane proteins to the lysosome. There are two processes that we examine: the first is how proteins are designated and recognized for delivery to the lysosome. The second is how transport through the endocytic pathway via endosome membrane fusion events is controlled.
Our primary focus is one finding out how individual “cargo” proteins are selected and designated for transport and degradation in the lysosome. Membrane proteins can initiate their journey to lysosomes from a number of cellular compartments. At the cell surface, proteins can enter the endocytic pathway via internalization. At the Golgi apparatus, proteins can be sorted into transport vesicles that are targeted to endosomes. Perhaps the most critical sorting step controlling the degradation of membrane proteins in lysosomes, is the incorporation of protein cargo into vesicles that bud into the lumen of the endosome. This sorting step occurs within endosomes and leads to the formation of multivesiculated bodies (MVBs) that accumulate lumenal membranes. These lumenal membranes are then subject to degradation by lysosomal lipases and proteases, thereby ensuring the complete destruction of integral membrane proteins.. A variety of studies in both yeast and mammalian cells have established that this sorting step is conferred by the post-translational attachment of ubiquitin, a 76 amino acid peptide that is covalently linked to lysine residues via an isopeptide bond.. Currently we are determining how ubiquitinated cargo is recognized and incorporated into transport vesicles destined for the lysosome.
Dr. McCray has a long-standing interest in the pathogenesis and treatment of cystic fibrosis. His laboratory has two main areas of investigation: 1) innate mucosal immunity in the lung and how this is altered in disease states, and 2) gene transfer for the treatment of inherited diseases.
Studies of the anti-microbial properties of the airway surface liquid have stimulated interest in the anti-microbial proteins and peptides secreted by epithelia. Dr. McCray's lab is currently defining the tissue specific expression, regulation and anti-microbial activity of epithelial defensins and other proteins in model systems. These molecules may play a role in the innate mucosal immunity of the lung and other mucosal surfaces. A major effort is directed towards identifying novel host defense genes using genomics and large scale expression profiling.
Another area of investigation is the development of integrating viral vectors for the treatment of inherited diseases. Current projects include gene transfer to airway epithelia for cystic fibrosis and gene transfer to the hepatocytes for the treatment of hemophilia A. The focus of these studies is on the development and optimization of retrovirus-derived vectors. A long-term goal is to develop strategies with integrating vector systems that could be successfully used to treat genetic diseases.
Research in my laboratory is aimed at understanding fundamental physiological properties of the eye and the pathophysiological mechanisms underlying a variety of complex eye diseases. Of primary interest are the glaucomas, a leading cause of blindness that affects approximately 70 million people worldwide. Glaucoma typically involves three types of events: molecular insults compromising the anterior chamber, increased intraocular pressure, and neurodegenerative retinal ganglion cell loss. Not surprisingly, the biological relationships linking these events are complex. Our approach for studying these events is founded in functional mouse genetics and supplemented by a variety of molecular, cellular, immunological, and neurobiological techniques. The premise for this approach is that stringently performed genetic studies offer great potential for overcoming the natural biological complexity of glaucoma. Current projects in the lab involve mouse models of pigmentary glaucoma and are testing the hypotheses that aberrant melanosomal processes and inflammation are potent contributors to this form of glaucoma. We are also interested in new mouse models of glaucoma and are developing mouse ES cell based genetic strategies for fostering the discovery of new glaucomatous mechanisms. In the long term, these studies will contribute to an increased understanding of eye diseases such as glaucoma, and ultimately to improved human therapies.
Learn fromtop-notch researchersat the University of Iowa
Iowa City, Iowa 52242 | 319-335-3500 | Nondiscrimination Statement