PHA Proof of Concept Research Grant Winner 2016
Kazuyo Kegan, PhD
Anesthesiology and Critical Care Medicine
Johns Hopkins University
Title: “Illuminating AMPK function in crosstalk between Insulin Resistance and Pulmonary Hypertension”
Term: December 1, 2016 – November 30, 2017
Summary of Research Project:
Pulmonary hypertension (PH) is a severe disease in which small pulmonary arteries thicken and pulmonary blood pressure increases. Over time, this condition puts a strain on the heart, leading to heart failure and death. Major advances in diagnosis and treatment of PH have been made over the last several decades, but the underlying mechanisms of PH are unclear and complex. Because of this complexity, the progress in PH drug development has been slow. Available treatments only alleviate symptoms, without eliminating the cause. Evidence suggests that an important association exists between PH and insulin resistance. Proteins known as 5′ adenosine monophosphate-activated protein kinase (AMPK) and insulin receptor substrate-2 (IRS2) are the most critical molecules in insulin resistance. Our goal is to unravel the unrecognized role of IRS2 and AMPK in the development of PH. We propose to determine how dysfunction of IRS2-AMPK interaction leads to PH disease cascades. To elucidate the specific roles of AMPK in the disease process of PH, we will use cutting-edge genetically encoded molecular sensors to analyze site-specific AMPK activity. Our goal is to develop a new therapeutic approach for restoring the IRS2-AMPK axis. This research may help us to develop new drugs that restore the function of this pathway and can be used to treat PH.