The focus of work in this laboratory is on the elucidation of the molecular properties and regulatory mechanisms controlling the function of G protein-coupled receptors. As model systems we utilize the so called adrenergic receptors for adrenaline and related molecules. The goal is to learn the general principles of signal transduction from the outside to the inside of the cell which are involved in systems as diverse as sensory perception, neuro- transmitter and hormonal signaling. Studies are performed with isolated protein, whole cells in culture and even in vivo in whole animals.
Current projects emphasize attempts to understand regulation of the receptors and their desensitization which occurs in response to persistent stimulation. We are isolating the enzymes and proteins involved in these processes and studying their mechanisms of action in isolated protein and cellular systems as well as in whole animals. Most important are special enzymes called G protein-coupled receptor kinases which phosphorylate the receptors and lead to their desensitization which occurs when they bind a second protein called barrestin. Most recently we have been developing lines of transgenic animals in which these various proteins are either overexpressed or "knockedout" by homologous recombination. These genetically altered animal lines are helping to shed new light on the ways in which receptors are regulated. They also have suggested several novel approaches to human therapeutics.
While no clinical trials are currently in progress in our program we are experimenting with novel approaches to the treatment of congestive heart failure in animal models. Specifically we are injecting recombinant adenovirus encoding either the b-adrenergic receptors or inhibitors of the b-adrenergic receptor kinase down the coronary arteries of rabbits. The hope is that these gene products when expressed in the myocardium will markedly enhance cardiac contractility.
Dr. Lefkowitz has received a great deal of recognition for his research including election to the National Academy of Sciences and the Institute of Medicine of the National Academy of Sciences as well as the receipt of numerous awards. Most recently these have included the The Louis and Artur Lucian Award for Research in Circulatory Disease, The Fred Conrad Koch Award - The Endocrine Society, The 2001 Jessie Stevenson Kovalenko Medal - The National Academy of Sciences and The Peter Harris Distinguished Scientist Award, International Society of Heart Research. Dr. Lefkowitz writes numerous review articles in the areas of hormone and drug receptors and their regulation and is a consultant for several drug companies which specialize in drugs which may affect signal transduction processes such as Norak, Lexicon Genetics and Genentech.
Education and Training
- M.D., Columbia University, 1966
- Integrated Training in Anesthesiology Research
- Multidisciplinary Heart and Vascular Diseases
- Organization and Function of Cellular Structure
- Pharmacological Sciences Training Program
- Interdisciplinary Training Program in Lung Disease
- Dissecting Receptor Signaling Pathways in Pulmonary Hypertension
- Functional consequences of different conformational states of beta-2-adrenergic receptor-beta-arrestin complexes
- Molecular Regulation of Cardiovascular 7 TM Receptors
- Optimizing Beta-Adrenoceptor Signaling Bias in Asthma
- Mechanisms of Maladaptation in Heart Failure
- Biophysical Analysis of ß2-Adrenergic Receptor and ß-arrestin1 complex
- Noncanonical Receptor Signaling in Pulmonary Arterial Hypertension
- Building Interdisciplinary Research Careers in Women's Health
- Modulation of Odorant Receptor Function
- Medical Scientist Training Program
- Duke Training Grant in Nephrology