Jeffrey Wine Ph.D.

Professor

Jeffrey J. Wine Professor of Psychology, Human Biology and (by courtesy) Pediatrics Department of Psychology and Cystic Fibrosis Research Laboratory Jordan Hall, Building 420 Stanford University, CA INSTITUTION AND LOCATION DEGREE University of Pittsburgh, PA BS 1965 Psychology UCLA, CA MA, PhD 1971 Physiological Psychology Stanford University, CA Post-Doc. 1972 Biology A. Personal Statement: I established and direct the cystic fibrosis (CF) Research Laboratory at Stanford. We do basic research designed to ameliorate CF lung disease. We have 2 projects: one to understand why the lungs of CF patients are so susceptible to infection, and the other to measure CFTR function in vivo with high accuracy. Our studies with human and animal lung tissue have centered on the role of submucosal glands and mucociliary clearance. We developed methodologies to study individual airway glands in situ 'the bubble method' and isolated, intact glands in vitro (with DIC imaging). We have identified fundamental defects in CF glandular secretions, including loss of responses to β-adrenergic stimulation and deficient responses to synergistic stimulation with cholinergic and adrenergic agonists. Recent efforts have pursued a massive synergistic effectiveness in mucociliary clearance (MCC) seen when calcium and cAMP agonists are combined and large increases in MCC when we inhibited ENaC. The second project to measure CFTR function accurately combines two methods that I developed. The first is the ratiometric expression of β-adrenergically stimulated, CFTR-dependent sweat rates over methacholine-stimulated CFTR-independent sweat rates, which gives a near-linear readout of CFTR function (i.e. average carrier values are half of average WT values). The second was to develop optical methods to apply this concept to individual sweat glands, and to develop optical methods to identify individual glands and track 50-100 glands per subjects for weeks or months while on and off drugs-a method that permits n-of-one studies to yield significant information. We are now applying these methods to evaluating the effects of various Vertex compounds on various mutations. My role in this project will be to supervise all aspects of the research: planning, experimental execution, data analysis and manuscript writing. B. Positions and Honors: Positions and employment: 1972-1978 Assistant Professor, Dept of Psychology, Stanford University 1978-1986 Associate Professor, Dept of Psychology, Stanford University 1987-2006 Professor (by courtesy), Molecular & Cellular Physiology, Stanford University 1986-present Professor, Dept of Psychology, Stanford University 2006-present Professor (by courtesy) Dept of Pediatrics, Stanford School of Medicine 2008-present Benjamin Scott Crocker Professor of Human Biology Other Experience and Professional Memberships: 1971 Grass Fellowship in Neurophysiology, Marine Biological Laboratory, Woods Hole 1977-78 Alfred P. Sloan Foundation Research Fellowship 1978-80 Editorial Board, Science 1978-88 Editorial Advisory Board, Journal of Comparative Physiology 1993-1999 Ed. Board, American Journal of Physiology, Lung: Molecular & Cellular Physiology 2003-2006 Director, Program in Human Biology, Stanford University 1988-present Cystic Fibrosis Foundation Research & Research Training Review Panel 2008-present Associate Editor, Journal of Cystic Fibrosis C. Contributions to Science 1. My laboratory is focused on understanding the origins of CF lung infections. Our hypothesis is that CF lungs will retain near normal function if infections can be held at bay. We further hypothesize that the susceptibility to lung infections is the result of abnormal airway mucus, which, because of the failure of CFTR-dependent, anion-mediated fluid secretion, is deficient in both its ability to arrest bacterial growth and to sweep bacteria from the airways. Through detailed work with intact submucosal glands (both from humans and animal models of CF) we have been able to demonstrate profound defects in glandular secretions that render them ineffective at maintaining a healthy airway surface. My laboratory pioneered the working models and methodology that permitted the study of bronchial gland secretions in great detail. This is helping to clarify the origins of CF lung disease. Our work questions the assertions that CF lung disease begins in the small airways. Thus, thanks to the methodology I developed a more clear understanding of the role that bronchial secretions abnormalities play in CF lung disease has been possible. 2. Because CFTR dysfunction is the root cause of CF and because disease severity can be improved by even small increases in CFTR function, an additional goal is to measure human CFTR function in vivo with greater accuracy that has been possible before. That is the direct goal of the research proposed here, with sweat gland function serving as the biomarker. My laboratory has pioneered the methodology to quantify in vivo and in real time the amount of CFTR function in people with and without CF, and in people taking CFTR-directed therapeutics, such as ivacaftor. We do this by measuring sweat rates from individual, identified sweat glands, and we will further develop and apply this methodology in the present proposal. The methodology I developed permits the study of single gland sweat secretion with a non-destructive assay. This permits the study of the same glands repeatedly over time, an important feature to evaluate with great detail longitudinal effects of CFTR modulator drugs. 3. In addition to the above contributions, I maintain active collaborations for the discovery and investigation of novel compounds with CFTR modulation activity. This has permitted the identification of compounds with important physiologic effects on the activity of mutated CFTR. These studies utilized a multiplicity of modalities and model systems to identify important drug effects and gain insight into mechanisms of action.

Appearances