Walter J. Koch

The Koch lab is a large, established research group that recently relocated to Duke University in August 2023.  Broadly, our lab studies translational therapies for heart failure. Specifically we are focused on the molecular mechanisms involved in the regulation of signaling through cardiovascular adrenergic receptors (ARs) including the specific in vivo interactions between ARs and myocardial G protein-coupled receptor kinases (GRKs).

Over the last several years, the Koch lab has been investigating the role of cardiovascular G protein-coupled receptor (GPCR) kinases (GRKs) in several in vivo model systems. Original studies were done in transgenic mice where GRK-based transgenes were targeted specifically to the heart. We have found that a two specific GRKs, GRK2 and GRK5, play significant roles in the development of pathological cardiovascular conditions such as ventricular hypertrophy and heart failure (HF). GRK2 has been found to be elevated in the heart following stress or injury and increased GRK2 is maladaptive and pathological. Indeed, we have shown that inhibition of GRK2 is therapeutic in several small and large animal models of HF and clinical trials with gene therapy and emerging small molecule inhibitors are on the translational horizon. GRK5 is also increased in failing human hearts and we have found pathological consequences of this up-regulation in the heart, although via distinct mechanisms from GRK2. Non-canonical (non-GPCR desensitizing) activity of both GRK2 and GRK5 appear to contribute to their pathology in the heart. For example, we have found GRK2 to be a pro-death kinase during acute ischemic injury in the heart as well as a negative regulator of insulin signaling and glucose metabolism in the heart. The pro-death activity of GRK2 appears related to its localization to mitochondria where it is found in all compartments of these organelles and accumulates after oxidative stress. GRK5 appears to be a target in pathological hypertrophy and HF due to its unique cellular localization in the nucleus of myocytes where it regulates pathological gene transcription. The interplay between GRK2 and metabolism is emerging as a novel critical element in cardiac and fat homeostasis. Our lab continues to elucidate specific classical and non-classical mechanisms of these two GRKs in the normal and compromised myocardium. We continue to use mouse models and viral-mediated gene delivery to test our hypotheses and to learn novel regulatory properties of GRKs.