Loss of islet beta cells and/or impaired beta cell function cause type 1 or type 2 diabetes - diseases that are increasing at an alarming rate to reach epidemic levels worldwide. The overarching goal of our research is to investigate mechanisms responsible for maintaining islet cell function and to devise new strategies for enhancing beta cell fitness and robustness to prevent or treat diabetes. Our research program is interdisciplinary and encompasses islet biology, zinc biology and chemical biology.
- Islet biology - maintenance of islet cell fitness and function
During the early phase of diabetes development, there is a gradual decline of beta cell function leading to impaired insulin secretion and glucose tolerance. As the disease progress, beta cells continue to decline to a point where the amount of released insulin no longer meets the metabolic demand, causing glucose to rise to a level at which diabetes can be diagnosed. Investigating how islet endocrine cells maintain their fitness and functionality to sustain appropriate hormone secretion is essential for understanding how beta cell fails in diabetes and for inventing new therapies to restore physiological glucose homeostasis.
We tackle the problem by asking whether there are functionally distinct subpopulations of islet cells, for instance, beta cells that maintain a robust insulin secretion activity in response to secretagogue stimulation. Investigating functional heterogeneity of islet cells is expected to shine light on how endocrine cells maintain their nutrient responsiveness and hormone secretion activity, and define molecular defects in cells that fail to mount hormone release in the face of physiological demands. We investigate islet cell heterogeneity using both mouse and human samples. Using a combination of methods including activity-dependent cell tagging, cell sorting and RNA-Seq, we are studying mouse islet beta cells derived from the peptide YY lineage (Pyy+ beta cells). For human islet cells, we have identified subsets of human alpha cells with distinct glucagon contents. We are analyzing these cells in great details to characterize their functional properties and to define their contributions to the islet hormone secretion and euglycemia control.
- Zn2+ biology - zinc transporters and regulation of zinc homeostasis
Zn2+ is an important transition metal playing essential roles in diverse biological processes. Malfunction of cellular Zn2+ homeostasis is implicated in a number of human diseases including diabetes. Recent genome wide association studies have uncovered that mutations of a Zn2+ transporter, ZnT8 (Slc30a8 gene), were associated with the risk of type 2 diabetes. ZnT8 is abundantly expressed in islet cells. Remarkably, haploinsufficiency of Slc30a8 is protective against diabetes, yet the underlying mechanism remains elusive. Using genetically engineered mouse models, we are investigating how variations in ZnT8 expression may affect diabetes susceptibility and islet cell function.
- Probe development and targeted drug delivery
In the arena of chemical biology, we focus on crafting fluorescent Zn2+ sensors for monitoring Zn2+ activity in different cellular compartments as a part of our efforts of studying Zn2+ signaling and the regulation of Zn2+homeostasis. To explore the translational potential of our research in islet biology and diabetes, we are developing strategies to enable targeted delivery of imaging probes or therapeutic agents to specific tissues or organs including islet b-cells.