Michael J. Welsh, M.D.

Professor of Medicine and Molecular Physiology & Biophysics

Investigator: Howard Hughes Medical Institute

University of Iowa, 1974

Research Interests

My laboratory puts emphasis in three main areas. The first is understanding the biology of cystic fibrosis, a common lethal genetic disease. We study the function of the CF gene product, CFTR, using a combination of electrophysiologic, biochemical, cell biology, and molecular biologic approaches. We are learning how single CFTR chloride channels are regulated and how they form a pore through which chloride flows. We use wild-type CFTR and variants containing site-directed mutations to probe the cell biology and function of the channel. We are also focusing on the pathogenesis of the disease, trying to understand how a loss of CFTR leads to airway infections. We hope to use this knowledge to develop novel treatments.

Second, we are developing gene therapy to treat cystic fibrosis and other genetic diseases. The two vector systems which we are currently using most extensively are adenovirus-based vectors and adeno-associated virus vectors. The studies include basic vectorology, preclinical studies, and studies in humans.

Third, we are studying the cellular and molecular biology of a class of ion channels that includes epithelial amiloride-sensitive Na⁺ channels (ENaC) and the degenerins in C. elegans. Our current work focuses on the function of these channels in the peripheral and central nervous system. In the peripheral nervous system we think these channels are involved as sensory receptors for a variety of stimuli, including the pain associated with acidosis, light touch, stretch of vessels, and salty taste. In the central nervous system we are investigating their role in osmosensation and in higher order integrative functions. To understand the biology of these channels, we are generating knockout and transgenic mice and Drosophila with mutation in these genes. Our studies extend from evaluation of the electrophysiologic function of single channel complex, biochemical analyses of the channel complexes and associated proteins, and analysis of their function in whole organisms. The results of this work will lead to a better understanding of neuronal sensory systems and novel targets for therapeutic interventions.

Selected Publications

1. Wemmie JA, Chen J, Askwith CC, Hruska-Hageman AM, Price MP, Nolan BC, Yoder PG, Lamani E, Hoshi T, Freeman JH, Jr, and Welsh MJ. The Acid-Activated Ion channel ASIC Contributes to Synaptic Plasticity, Learning, and Memory. Neuron, 34:463-477, 2002.

2. Singh PS, Parsek MR, Greenberg EP, and Welsh MJ. A Component of Innate Immunity Prevents Bacterial Biofilm Development. Nature 417:552-555, 2002.

3. Walters RW, Freimuth P, Moninger, TO, Ganske I, Zabner J, and Welsh MJ. Adenovirus Fiber Disrupts CAR-Mediated Intercellular Adhesion Allowing Virus Escape. Cell 110:789-799, 2002.