Research Program

Research in the Coate laboratory seeks to identify mechanisms regulating the cell-specific molecular and functional properties of human pancreatic islet cells in health and disease.

The physiological, cellular, and molecular mechanisms that govern the function and maintenance of human pancreatic islet endocrine cells in healthy individuals remain poorly defined. Furthermore, we do not know what causes these cells to become dysfunctional during the development of metabolic diseases such as type 2 diabetes (T2D). The last decade has witnessed not only improved access to human pancreatic tissue but also dramatic expansion in the number of tools that enable interrogation of cell-specific features with unprecedented molecular, spatial and temporal resolution. By integrating these modalities in a team science-based approach, the potential for scientific discovery is greater than ever before!

The overarching goal of my research program is to integrate advanced genetic, genomic and physiological approaches to advance our knowledge and understanding of mechanisms that regulate the activity and identity of human pancreatic islet cells in health and disease.

Our research is guided by the following questions:

1. What are the gene regulatory factors that control pancreatic cell type-specific function and maintenance in adult human islets?
2. How do unique features of pancreatic cell types influence their response to (patho)physiologic challenges in vivo (e.g. obesity and T2D)?

Current projects in the lab include:

1. Defining how islet-enriched transcription factors (TFs) impact gene regulation and function in adult human alpha and beta cells.  Studies principally performed in mice have established critical roles for pancreatic islet-enriched TFs in alpha and beta cell development and function. Strikingly, most (if not all) forms of diabetes are associated with islet-enriched TF inactivity. We are investigating the role of one such TF, MAFB, which we have found to be an important regulator of the molecular and functional identity of human alpha cells. Analogous studies are also underway for ISL1, another islet TF linked to obesity and T2D.
2. Determining how lipid droplets (LDs) regulate human alpha and beta cell fitness under normal and pathological conditions. LDs are dynamic intracellular organelles that affect many aspects of cell physiology and adaptively increase in response to cellular stress. LDs uniquely accumulate in human (as opposed to rodent) pancreatic islets in an age- and disease-dependent manner and appear to be critical in maintaining human beta cell function and health. Our recent data highlight a regulatory role for LDs in controlling the physiological function of human alpha cells as well. Studies are underway to test the hypothesis that LD accumulation is part of the adaptive response to metabolic stress that protects human islet cells challenged by glucose and/or lipid-induced toxicity.