Kenneth Humphries, Ph.D.
PhD Physiology & Biophysics 1995-2000, Case Western Reserve University, Cleveland, Ohio
BS magna cum laude in Chemistry, minor in Mathematics, Honors Scholar 1995, John Carroll University, University Heights, Ohio
Aging is associated with an increased risk of diabetes. Furthermore, cardiovascular disease is the most prevalent cause of morbidity and mortality in diabetic patients and its incidence also increases with age. Diabetes can directly damage the heart and this is referred to as diabetic cardiomyopathy. The research in my laboratory is focused on understanding how diabetes leads to this cardiomyopathy so that better treatment options can be developed.
A major focus of the lab is determining how the beta-adrenergic signaling pathway is affected by diabetes, and how these changes may exacerbate and enhance stress on the heart. Activation of cAMP-dependent protein kinase (PKA) via beta-adrenergic receptor signaling is a primary means of increasing cardiac contractility. Over-activation or dysregulation of this pathway is a major driver of diabetic cardiomyopathy, life threatening arrhythmias, and heart failure. However, the mechanisms by which this pathway becomes disrupted are largely unknown. In the healthy heart, PKA increases contractility by amplifying calcium cycling and concertedly activating phosphofructose kinase-2 (PFK-2) to promote glucose oxidation. In this manner, workload and metabolic demand are finely orchestrated. We have identified important changes in both PKA signaling and PFK-2 activation that may drive diabetic cardiomyopathy. Ongoing studies are determining the molecular mechanisms of this signaling dysfunction to identify potential points of intervention.
Another long standing interest of my lab is identifying how mitochondrial function is affected by diabetes. The heart’s constant demand for energy is primarily derived from fatty acids and secondarily from glucose. Diabetes leads to metabolic inflexibility, in which the capacity of the heart to use glucose is greatly diminished. While changes in glucose metabolism occur in the cytoplasm, we have shown that there are alterations in mitochondrial function that further promote metabolic flexibility. This may be an important determinant in the occurrence or progression of diabetic cardiomyopathy. We have shown that these changes in mitochondrial function are mediated, in part, by overabundance of acetylated proteins. We are working to understand how hyper-acetylation occurs, how it affects mitochondrial function, and how it can be alleviated. There are currently no therapeutics that specifically target mitochondrial abnormalities and diabetic cardiomyopathy. The results of this research will determine if preventing or reversing mitochondrial acetylation is a promising target for therapeutic intervention.
Kenneth Humphries, Ph.D.
Satoshi Matsuzaki, Ph.D.
Craig Eyster, Ph.D.
Jennifer Giorgione, Ph.D.
Albert Batushansky, Ph.D.
senior research technician