Walter J. Koch, Ph.D.

Contact Dr. Koch

Center for Translational Medicine
1025 Walnut Street, Suite 317
Philadelphia, PA 19107

(215) 955-9982
(215) 503-5731 fax

Fellowship
Duke University Medical Center and Howard Hughes Medical Institute

Degree
Ph.D. Pharmacology and Cellular Biophysics, University of Cincinnati, College of Medicine 1990

University Appointment
W.W. Smith Professor of Medicine (with Tenure), 2003

Research and Clinical Interests
The Koch laboratory currently is investigating molecular mechanisms involved in the regulation of signaling through cardiovascular adrenergic receptors (ARs) and the role this plays in heart disease, primarily heart failure (HF). The lab's research primarily targets a family of kinases known to regulate ARs and other G protein-coupled receptors (GPCRs) known as the GPCR kinases (GRKs). These GRKs appear to be critically involved in normal and failing heart function and we are manipulating the expression and activity of GRKs in the cardiovascular system. To do this, we utilize novel genetically engineered mouse models and also viral-mediated myocardial gene delivery. We focus our efforts on two GRKs important for myocardial signaling, GRK2 (also known as ARK1) and GRK5. Signaling information delineated to be involved in the pathogenesis of heart disease is utilized to design potential novel molecular therapeutic strategies for heart disease. This includes an ultimate goal of the laboratory to develop gene therapy protocols for HF utilizing novel intracoronary delivery techniques. These delivery techniques as well as "proof of concept" testing of molecular targets in the heart are currently being carried out in vivo in both small and large animal models of HF. In addition to HF, programs are ongoing in the laboratory to investigate novel ways to protect the heart against ischemia-induced myocyte apoptosis and also investigation into the cross-talk between the adrenal gland and the sympathetic nervous system with the heart during the pathogenesis of HF. New directions in the lab have us interested in novel non-GPCR binding partners for GRKs as well as novel cellular localization such as the nucleus for GRK5 and mitochondria for GRK2. Finally, our clinical research focuses on the use of blood levels of GRK2 as a prognostic and diagnostic biomarker in cardiovascular disease.

Publications

Most Significant Peer-reviewed Publications

1. An adrenal β-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo
2. Myocardial adeno-associated virus serotype 6-βARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure
3. Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes
4. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure
5. Targeted inhibition of cardiomyocyte Gi signaling enhances susceptibility to apoptotic cell death in response to ischemic stress
6. Regulation of β-Adrenergic Receptor Signaling by S-Nitrosylation of G-Protein-Coupled Receptor Kinase 2
7. Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure
8. Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure
9. β-adrenergic receptor-mediated DNA synthesis in cardiac fibroblasts is dependent on transactivation of the epidermal growth factor receptor and subsequent activation of extracellular signal-regulated kinases
10. Targeting the receptor-G(q) interface to inhibit in vivo pressure overload myocardial hypertrophy