Michael CascioAssociate Professor
Bayer School of Natural and Environmental Sciences
Chemistry and Biochemistry
Education:Ph.D., Biochem. & Mol. Biophysics, Columbia University, 1988
M.A., Biochem. & Mol. Biophysics, Columbia University, 1984
B.A., Chemistry and Biology, Cornell University, 1981
The major research interest of my laboratory is the correlation of structure and function for membrane protein receptors and channels, primarily neuroreceptors. Utilizing recent biotechnological advances, we successfully overexpressed recombinant human glycine receptors in insect cells at a fairly high level. This receptor is part of a superfamily of ligand-gated ion channels critical in transmission of synaptic signals. Using circular dichroism, and mass spectrometry coupled with chemical modification, we critically examined the topology and structure of this paradigmatic ion channel. In order to continue to characterize the structure of this ion channel, our lab is systematically incorporating cysteine residues at select regions of the receptor and incorporating non-specific crosslinking and cleavage reagents (to map accessibility and proximity using mass spectrometry as a structural tool), fluorescent tags, and spin labels (these latter studies are in collaboration with Dr. Sunil Saxena, Dept. of Chemistry, University of Pittsburgh). We are also engaged in studies examining the effects of lipid composition on the structure and function of the glycine receptor. Crystallographic trials of a soluble form of the extracellular domain of this receptor are also being conducted. Our lab has also initiated collaborative computational studies of the glycine receptor with the laboratories of Dr. Rob Coalson (Dept. of Chemistry, University of Pittsburgh), Dr. Maria Kurnikova (Dept. of Chemistry, Carnegie Mellon University) and Dr. Vasanthi Jayaraman (University of Texas Health Science Center, Houston, Texas). Studies with Dr. Glorioso (past chair of my department at University of Pittsburgh) and a large interdisciplinary team at the University of Pittsburgh seek to develop gene delivery of glycine receptors to peripheral nerves as a way to effectively alleviate pain.
Our laboratory also collaborates extensively with faculty both at the University and at other institutions on other projects, some of which are briefly described below. We have recently begun collaborating with an established team of researchers at Duquesne University that are examining the structure and pharmacology of dopamine and serotonin transporters. This team includes Dr. Jeffry Madura, a computational chemist in my department, as well as Drs. David Lapinsky and Chris Surratt in the School of Pharmacy. We have initiated crosslinking studies coupled with mass spectrometric analyses to investigate the binding site of novel photoactivatable drugs that modulate transporter activity.
In collaboration with Dr. Terri Hastings (Dept. of Neurology, University of Pittsburgh), protein targets that are selectively modified by dopamine under oxidative conditions in a Parkinson's disease model have been identified with the aim to develop novel protective therapies and understand the etiology of this neurodegenerative disease. These studies utilize 2D gel electrophoresis (DIGE) coupled with mass spectrometry to identify mitochondrial and cellular proteins whose cysteinyl residues become oxidized under oxidative stress or in model Parkinson's systems. In addition, we are examining amyloidogenesis in Alzheimer's Disease. Amongst its many natural targets, neprilysin and other Zn+2-dependent proteases have been shown to cleave fibril-forming Abeta peptide both in vitro and in vivo. By engineering the active site of a truncated secreted form of these enzymes, we aim to create an Abeta-selective protease that may be used in combating Alzheimer's disease. These studies are being conducted in collaboration with Dr. Marc Glucksman (Rosalind Franklin School of Medicine) and Dr. Joseph Glorioso (University of Pittsburgh).
|2009 - present||Director and lecturer||CHEM 401/501||Biochemistry I|
|2010 - present||Organizer||CHEM 588||Research in Progress seminar|
|2010 - present||Co-Director and lecturer||CHEM 566||Mass spectrometry|
|2010||Lecturer||CHEM 510||Bioanalytical Chemistry|
|2011 - present||Co-Director and lecturer||CHEM 527||Biochem. Biophys. Char. Macromol.|
|2012||Director and lecturer||CHEM 402/502||Biochemistry II|