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Our lab investigates diabetes and metabolic disorders, focusing on their links to cardiovascular and neurodegenerative diseases. Using tools ranging from single-molecule imaging to whole-animal genetic models, we aim to uncover mechanisms and develop innovative therapies for conditions such as diabetes, heart failure, and Alzheimer’s disease.
Distinct binding of Aβ and catecholamine to β2AR.
The CNS insulin and adrenergic regulation and in Alzheimer’s disease and Parkinson disease.
Metabolic disorders and diabetes are associated with a higher incidence of neurodegenerative diseases. Insulin resistance, in particular, has been linked to both Alzheimer’s disease and Parkinson’s disease. Our recent work revealed that soluble amyloid-β peptide acts as a partial allosteric agonist for the CNS β₂-adrenergic receptor in the pathogenesis of Alzheimer’s disease. We hypothesize that amyloid-β promotes insulin resistance through degradation of the β₂-adrenergic receptor in the brain, thereby initiating a cascade of signaling events that drive synaptic dysfunction and neuronal degeneration.
Spatial distribution of two subpopulation of β2AR in neurons
The CNS adrenergic signaling in stress, PTSD, memory, and learning
Using sophisticated SiMPull, we have discovered that the β₂-adrenergic receptor exists as two distinct subpopulations within a single hippocampal neuron. These subpopulations are defined by site-specific phosphorylation mediated by either PKA or GRKs in response to agonist stimulation. The PKA-dependent phosphorylation is required to enhance LTCC activity and synaptic excitability, whereas The GRK-dependent phosphorylation directs signaling to the nucleus, promoting gene expression programs that underlie memory formation, learning, and inflammatory responses.
Regulation of intracellular β1AR-Serca2a in the heart.
Intracellular cardiac GPCR signaling in HFpEF.
We have been systematically characterizing intracellular signaling pathways triggered by GPCRs, RTKs, and cytokines. Building on this foundation, we extended our studies to investigate neurohormonal regulation of the cardiac inflammasome and ER stress in heart failure, with a particular focus on HFpEF. Our findings identify intracellular β₁-adrenergic receptors as a critical regulator driving the pathological development of HFpEF.
InsR forms a functional signaling hub with β2AR.
Hyperglycemia and hyperinsulinemia in diabetes and diabetic complications.
Hyperglycemia and hyperinsulinemia are hallmarks of type 2 diabetes. Hyperinsulinemia is associated with poor prognosis and increased mortality in patients with comorbid diabetes and cardiovascular disease; however, little is known about how insulin may exacerbate cardiovascular dysfunction. Our goal is to characterize novel mechanisms underlying the effects of hyperglycemia and hyperinsulinemia on multiple tissues in the context of metabolic disorders and aging. In addition, we aim to uncover new GPCR regulatory mechanisms that govern glucose metabolism and insulin resistance in obesity and aging.
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