The Chatham Lab

From: https://doi.org/10.1152/physrev.00043.2019

Our laboratory aims to understand how cardiomyocytes respond to stress, particularly in the context of ischemia, diabetes, and heart failure. A major area of interest is how the modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) influences cellular function. Another focus of the laboratory is understanding the role of the calcium signaling protein stromal interacting molecule 1 (STIM1) on cardiomyocite function and how this is altered in response to diseases such as diabetes.

Mission

To explore fundamental physiological mechanisms that regulate cardiomyocyte homeostasis and determine how these respond to stress and contribute to cardiac disease, while providing an inclusive, creative, and rewarding environment that leads to success for all involved.

Research Overview

Cardiac energy metabolism is a tightly regulated process, which ensures that contractile function can be maintained under a wide range of demands on a daily basis throughout life. Alterations in cardiac metabolic regulation are linked to different types of heart disease including myocardial infarction, cardiac hypertrophy, and complications associated with diabetes.

The Chatham Lab has had a long-standing interest in whether these changes in metabolism contribute to the pathogenesis of cardiac disease. The post-translational modification of serine and threonine residues on nuclear, cytosolic, and mitochondrial proteins by a single, O-linked β-N-acetyl glucosamine (O-GlcNAc) moiety, is regulated in part by glucose availability and its metabolism via the hexosamine biosynthesis pathway (HBP).  For more than 15 years, the Chatham Lab has been studying the role of O-GlcNAc as a potential mechanism for transducing changes in metabolism into alterations in cardiomyocyte function. We have demonstrated that acute activation of O-GlcNAc levels is remarkably cardioprotective; conversely, in the setting of diabetes where O-GlcNAc levels are chronically elevated cardiomyocytes cell signaling pathways are impaired in an O-GlcNAc dependent manner.  We also found that cardiomyocyte calcium signaling is regulated in part via O-GlcNAcylation of stromal interacting molecule 1 (STIM1), a protein that is located in the endoplasmic and sarcoplasmic reticulum (ER/SR).  STIM1 is widely recognized as playing a key role in calcium signaling in non-excitable cells; however, its function in cardiomyocytes is poorly understood. We demonstrated that a STIM1 deletion specifically in cardiomyocytes resulted in metabolic and mitochondrial dysfunction ultimately leading to a dilated cardiomyopathy.  These were the first studies to demonstrate that STIM1 is essential for regulating cardiomyocyte homeostasis.

Collaboration is a core value of the Chatham Lab and this has resulted in grants and papers with other research groups at UAB and elsewhere on the role of O-GlcNAcylation in the regulation of a variety of cellular functions such as circadian rhythm, neurodegeneration, neuronal communication/synaptic function, cancer biology, cardiac remodeling, cardiac metabolism, as well as developing new techniques in quantifying glucose metabolism via the hexosamine biosynthesis pathway.