Research

Research in my lab focuses on the functions of a family of GPCRs (adrenergic receptors) in two areas: heart and Alzheimer diseases. GPCRs are nature's most versatile biological sensors. They conduct the majority of transmembrane responses to hormones and neurotransmitters, and mediate the senses of pressure, sight, smell, and taste. Adrenergic receptors, which transmit signals in both central and peripheral nerve systems, are one of the most extensively characterized subfamilies of GPCRs, and serve as a model system for understanding the structure, cell biology, and physiology of GPCRs. We are investigating adrenergic receptors using in vitro and in vivo systems to determine the structural and cellular basis for more complex functional properties in differentiated cells.

In animal heart, from studies of b adrenergic receptor knockout mice, we found that b1 and b2 adrenergic receptors play unique roles in regulating cardiovascular function, and are associated with heart failure development. We are using neonatal myocytes, sympathetic ganglia neurons from b1/b2 adrenergic receptor double knockout mice as a differentiated expression system to study the structural and cellular basis for the receptor functional properties. Our studies suggest that functional differences between two receptors are due to their distinct localization on post-synaptic cardiac myocyte cell surface relative to synapse formation between sympathetic neurons and cardiac myocytes.  Meanwhile, we examine the receptor signaling in more physiological relevant adult myocytes.

The second area we are interested in is the roles of adrenergic receptors in neuronal degeneration diseases: Alzheimer Diseases and Parkinson Diseases. In one project, we have found that amyloid Ab peptide directly activates b2AR in vitro. Ab activate bAR receptor  to induce cAMP accumulation in glia astrocytes, which induces gene expression of ApoE and APP, two key proteins involved in Alzheimer Diseases. Another project focuses on the interaction between G-protein receptor kinase 2 (GRK2) and a-synuclein, a key protein in Parkinson Diseases. We try to understand how the interaction affects the GRK2 activities, subsequent bAR and other GPCR (such as dopamine receptor) function in neuronal tissues. We are expanding these new and exciting projects to find out the cellular and functional roles of  bAR signaling in both glia and neuronal cells, and their roles in pathogenesis of Alzheimer and Parkinson diseases.

To carry out the outlined research projects, we have integrated molecular and cellular techniques, transgenic animals with high resolution single molecule living-cell imaging and real-time physiology. This powerful combination enables us to "envision" the complex and the beauty of the receptor signaling in physiological and pathophysiological processes. Our studies shall yield critical information on drug design and gene therapy on both cardiovascular and neuronal diseases.

Our current research focuses on five different areas:

1. Ligand-dependent adrenergic receptor action.

 

This is to characterize the signaling complexes associated with b1 and b2 adrenergic receptors in cardiac myocytes, and structural basis for the association under distinct agonist simulation. Our recent publication reveals that norepinephrine and epinephrine activates b2 adrenergic receptors to couple to distinct G protein signals through modulating GRK2-dependent receptor phosphorylation in cardiac myocytes. These studies for the first time to show biochemical evidences on how these two endogenous ligands act on the receptor signal for physiological contraction responses.

 

2. High resolution imaging of single receptor activation and cAMP/PKA pathways.

 

We use live cell imaging to study single receptor activation, second messenger event (i.e. cAMP, PKA, and Ca²⁺ signaling), and their significance in myocyte contraction and myocyte apoptosis. Our current progress leads us to observe for the first time the activation of distinct pools of a GPCR  in a single living cardiac myocyte. We are currently address the implication of such distinct signals induced by the same GPCR.

 

3. Functional adrenergic synapses between SGN and myocyte or ES-derived myocytes.

 

Adrenergic synaptic regulation of b1 and b2 adrenergic receptor cellular and signaling properties within the model system of co-culturing sympathetic ganglia neurons and cardiac myocytes. We will try to understand formation of neuron/muscular synaptic formation, and its influence on the adrenergic receptor function. In parallel, we are also trying to co-culture of sympathetic ganglia neurons and human ES derived cardiac myocytes to study the signaling network controlling myogenesis.

 

 

4. Crossing talk between b and a1 adrenergic receptors for cardiac hypertrophy.

 

Our recent studies have revealed distinct cross-talking between b and a1 adrenergic receptors in both cardiac myocyte and cardiac fibroblast cells. In particular, b adrenergic receptors control the a1 adrenergic receptor dependent hypertrophic signaling for muscle cell growth both in vitro and in vivo.

 

 

5. Adrenergic receptor signaling in Alzheimer disease.

 

We have identified b2 adrenergic receptors as a receptor for the amyloid peptide in vitro and on cell cultures. We are examinng the functional implication of the receptor signaling induced by amyloid Ab peptide in both glia and neurons. We will try to determine whether the receptor signaling is involved the disease progress.

 

These studies will help us understand the signaling properties of the receptors at cellular levels, and may provide new approaches to intervene the receptor functions in variety of clinical conditions such as heart failure and hypertension, as well as Alzheimer diseases.