Current Research

Research in the Walsh laboratory has been focused in three areas. The major project investigates the signaling- and transcriptional-regulatory mechanisms that control both normal and pathological tissue growth in the cardiovascular system. Many of these studies involve analyses of the PI3-kinase/Akt/GSK/Forkhead signaling axis. This pathway is of critical importance in the regulation of organ growth and body size. Signaling through this pathway controls cellular enlargement (hypertrophy), cell death (apoptosis), and blood vessel recruitment and growth (angiogenesis). We have shown that the PI3-kinase/Akt/GSK/Forkhead signaling axis regulates multiple steps critical in angiogenesis including endothelial cell apoptosis, differentiation, nitric oxide production and migration. We have also shown that some of these signaling steps are important for cardiac hypertrophy during normal postnatal development, and that they regulate myocyte survival in models of heart disease.

The second project investigates the role of the immune system in vascular disease. The formation of atherosclerotic lesions involves inflammatory cell interactions within the endothelium and subsequent extravasation into the vessel wall. Accelerated atherosclerosis is a critical factor contributing to the stroke and coronary heart disease that is a major cause of death among young women with systemic lupus erythematosus (SLE). Currently, there is considerable controversy regarding the causes of accelerated atherosclerosis in patients with SLE, although chronic inflammation is likely to be a contributing factor. To better understand these pathophysiological processes we created a new mouse model of atherosclerosis where lesion formation appears to be more dependent upon immune function than the standard apoE-/-model. Our findings suggest the existence of positive feedback interactions between atherosclerosis and the immune system that can develop when peripheral tolerance is breeched. Further applicaion of this model could be valuable in delineating the roles of the immune system in modulating the development of atherosclerotic lesions.

The third project analyzes the actions of adiponectin on cardiovascular tissues. It is now recognized that adipose tissue functions as an endocrine organ and that obesity contributes to cardiovascular and metabolic disorders through an imbalance of cytokines. Adiponectin is an adipocyte-derived cytokine that is down-regulated in obese individuals. Hypo-adiponectinemia is an independent risk factor for the development of diabetes, hypertension and coronary artery disease. We have found that adiponectin has beneficial actions on the cardiovascular system by directly acting on the heart and blood vessels. These data indicate that short-term administration of adiponectin, a natural cardioprotectant, could have utility for the treatment of acute cardiovascular disease.

Recently, we have developed mouse models to study the interrelationships between adipose and skeletal muscle tissues. We have isolated a number of novel proteins that are secreted during muscle growth. Analysis of these factors could provide insights about the pathogenesis of metabolic and cardiovascular diseases.

-Kenneth Walsh, Ph.D

August, 2006

Figure 1. Mechanism of Akt activation and partial list of downstream molecules.

Akt is activated by growth factors or cytokines in a PI3K-dependent manner, and phosphorylation of two residues by PDK1 (T308) and PDK2 (S473) is required for its full activation. Downstream target molecules are grouped according to their function. Note that these downstream molecules include both direct Akt substrates and indirect downstream effectors.