Research Interest

Patients with diabetes are at significantly increased risk for both microvascular and cardiovascular adverse events. This is because diabetes promotes disease in nearly all blood vessel types and sizes. Vascular complications are responsible for most of the morbidity, hospitalizations, and mortality in patients with diabetes. Dysregulated endothelial function is one of the major factors contributing to the development of vascular complications in diabetes. By using cell culture and mouse models, our lab explores endothelial regulated pathways that lead to dysmetabolism, a characteristic of metabolic disorders, including diabetes, insulin resistance, and obesity. Our previous research investigated the roles of endothelial regulation on peripheral angiogenesis and dysregulated inflammation in diabetes. As a logical extension to these studies, our current research centers on mechanisms underlying the endothelial regulation of metabolic disorders. Our long-term goal is to translate our bench-side pre-clinical findings to the bedside clinical practice, by providing insights into the development of much-needed management and therapy for these disorders.

Mechanisms regulating peripheral angiogenesis in diabetes mellitus
In diabetes, impaired physiological angiogenesis delays wound healing, exacerbates peripheral limb ischemia, and can even cause cardiac mortality due to a lack of collateral vessel development. However, effective therapies to restore peripheral angiogenesis are elusive. It is unclear how diabetes regulates angiogenesis. We recently found that methylglyoxal (MGO), a metabolite elevated in patients with diabetes, impaired angiogenesis by reducing protein levels of vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 is a key angiogenic protein that is downregulated in patients with diabetes and in diabetic mouse models. Our published data showed for the first time that VEGFR2 could be reduced by MGO-activated autophagy in cultured endothelial cells. Building on these data, we seek to understand the role and mechanism of autophagy in diabetic angiogenesis impairment, focusing on autophagy-mediated endothelial cell proliferation, matrix degradation, migration, tube formation, and vessel maturation affected by diabetes. Our goals will be achieved through experiments using genetic and pharmacological approaches in cell culture and mouse models of diabetes. With these approaches, we have identified endothelial autophagy-dependent and independent pathways regulating angiogenesis in diabetes.

Mechanisms modulating inflammatory response in diabetes mellitus
Inflammation is a characteristic of both type 1 and type 2 diabetes. Overwhelming evidence demonstrates the association of oxidative stress with vascular inflammatory response in hyperglycemia through mechanisms that are not fully elucidated. Protein degradation by the ubiquitin-proteasome system is central to cell homeostasis and survival. Defects in this process are associated with cancers and neurodegenerative disorders. However, the role of the ubiquitin-proteasome system in diabetes remains largely unknown. Using a proteasome reporter mouse model, we provided the first evidence that early hyperglycemia enhanced 26S proteasome functionality, contributing to elevated endothelial inflammatory response in diabetes. By monitoring 26S proteasome functionality in various mouse models of diabetes, we have identified new endogenous regulators (e.g., eNOS-derived nitric oxide), and new substrates (e.g., O-linked-GlcNAc transferase) that are relevant to vascular inflammation. Consequently, we have begun to understand the significance of protein homeostasis (proteostasis) in diabetes, which could provide insights into the development of therapeutic strategies for diabetes-associated dysregulated inflammation.

Mechanisms causing metabolic dysfunction in diabetes, obesity, and insulin resistance
An increasing body of evidence supports the evolving concept that functional interactions between organs/tissues are essential for metabolic homeostasis. Understanding the cause of metabolic dysfunction and diabetes will also require a detailed understanding of how these different tissues and organs work together. The endothelium forms the inner cellular lining of blood vessels by highly metabolically active endothelial cells. The endothelium has long been regarded as an integrated system, like an organ; however, the role and mechanism of endothelium in metabolic homeostasis has just emerged. Our previous studies of the endothelial regulation of cardiovascular complications in diabetes have set a stage on which we will be able to test the role and mechanism of endothelial cross-talk with metabolic organs and tissues. We expect to achieve these goals with genetic and pharmacological approaches in cell co-culture and mouse models of diabetes, obesity, and insulin resistance. Our pilot studies have revealed unexpectedly complex modes of endothelial interactions with metabolic organs/tissues, depending, at least in part, on duration of disease (e.g., diabetes and/or obesity) and locations of impacts (e.g., fat, liver, or skeletal muscle), which warrants further investigations of their clinical implication and translation.