Current Research Interests

The cGMP-dependent protein kinase (PKG) is an essential regulator of cellular function in blood vessels throughout the body. We seek to ascertain the molecular mechanisms of vascular control involving PKG and its signaling partners. Understanding how blood vessels constrict and dilate is critical for the development of new strategies and therapeutic agents aimed at prevention and treatment of vascular disorders such as hypertension, stroke and coronary artery disease. To achieve these goals my laboratory is currently working on three main research areas: cGMP-Biosensors, Inhibitors and Activators of PKG and structure/function Analysis of the cGMP signaling system. The individual projects within these main research areas are:

Intracellular cGMP and Ca2+ regulate vascular smooth muscle (VSM) function in health and disease. The emerging view is that intracellular Ca2+ signals are highly dynamic, and that patterning of Ca2+ signals determines VSM function. Understanding of intracellular cGMP signaling dynamics, subsequent activation of cGMP-dependent protein kinase (PKG), and its relationship to Ca2+ signals has lagged. Using novel cGMP biosensors, we have provided evidence that cGMP, like Ca2+, is spatially and temporally dynamic, and dependent on multiple interrelated control mechanisms.

- The Dynamics and Regulation of cGMP and Calcium in Vascular Smooth Muscle Contractility
- The Intracellular Patterning of cGMP in Primary Vascular Smooth Muscle Cells
- FlincGs: novel, non-FRET cGMP biosensors with nanomolar sensitivity for NO-induced signaling
- Novel strategies for the design of fluorescent biosensors

This project aims to determine the contributions of PKG to vascular control in vivo by studying the efficacy of PKG inhibitors to increase blood pressure and vascular resistance in isolated blood vessels and in the intact animal.

- Probing vasomotor mechanisms by acute inhibition of PKG in vivo
- Development of Novel PKG inhibitors
- Development of Novel PKG Activators

Here we continue our long standing interest in the basic architecture of PKG. A series of projects have been designed to gain insight into the structure-function of distinct functional domains of PKG as well as the entire kinase.

- The hinge region operates as a stability switch in cGMP-dependent protein kinase I
- cGMP Binding Site Mutants Define the Molecular Mechanism of PKG Activation
- Mass-spectrometry analysis of PKG using photo-affinity labeled PKG inhibitors
- The crystal structure of cGMP-dependent protein kinase