The Duke Cardiovascular Research Center announced that three projects led by CVRC faculty have received Mandel Seed Awards.
With awards beginning in 2006, the Mandel Foundation has provided more than $10 million to support multiple programs and researchers working to advance the state of knowledge and develop new avenues for treatment in hypertension, atherosclerosis, and related cardiovascular diseases.
"This sustained investment has significantly strengthened and deepened research within the Duke Cardiovascular Research Center. These most recent awards will continue this important work, funding a new generation of research projects and researchers," said Maria Rapoza, PhD, executive director of the Duke CVRC.
The following faculty are recipients of 2020 Mandel Seed Awards:
Neil J. Freedman, MD, and Christopher L. Holley, MD, PhD
Project: Atherogenic Mechanisms of Small Nucleolar RNAs
Atherosclerosis fundamentally involves oxidation, a chemical process that occurs normally in healthy cells but that, in excess, can derange the chemical structure of lipids and proteins and thereby adversely affect their function. The pathogenesis of atherosclerosis initiates with oxidation of the cholesterol-rich low-density lipoprotein particles, and perpetuates with excessive oxidative cell signaling— termed “oxidative stress”—in the inner layers of the artery. This project aims to attenuate excessive oxidative signaling through a novel regulatory mechanism involving particular RNA molecules known as small nucleolar RNAs, or “snoRNAs”, which are expressed throughout the body’s cells. We have found a group of snoRNAs that augment cellular oxidative stress, and we hypothesize that by interfering with the function of these snoRNAs we can mitigate atherosclerosis. For this purpose we will use mice that lack these particular snoRNAs, or “sno-knockout” mice, to build on findings from the first year of Mandel Foundation support for this project. We will compare aortic and brachiocephalic artery atherosclerosis between atherogenic Apoe-/- mice that are either sno-knockout or control (which express normal levels of the snoRNAs). We recently found that these snoRNAs promote chemical modification (methylation) of specific messenger RNAs. For this reason, we will determine which messenger RNAs are modified by our snoRNAs in smooth muscle cells and macrophages, to discern possible molecular mechanisms by which these snoRNAs exacerbate oxidative stress in cells and thereby aggravate atherosclerosis. Novel results from these studies may ultimately have therapeutic implications for patients with atherosclerosis.
Ravi Karra, MD, collaborating Christopher Kontos, MD
Project: Modeling the myovascular niche using human induced pluripotent stem cells
The heart is made up multiple cell types including muscle cells, called cardiomyocytes, and cells that line the blood vessels, called endothelial cells. Cardiomyocytes and endothelial cells are tightly coupled and make up myovascular niches within the heart. Interactions between cardiomyocytes and endothelial cells are critical to heart development, heart function, and the progression of heart failure. Thus, a better understanding of how cardiomyocytes and endothelial cells interact can lead to new treatments for cardiovascular disease. Here, we present work to develop an in vitro model of the myovascular niche and to identify novel mechanisms for regulating cardiac growth and regeneration.
Sudha Shenoy, PhD, collaborating with Jonathan Campbell, PhD
Project: The role of ubiquitination in glucagon-induced signaling bias and insulin secretion
Type 2 diabetes (T2D) and associated insulin resistance contribute to the etiology of atherosclerosis and constitute major risk factors leading to morbidity and mortality from cardiovascular disease. The peptide hormone glucagon and the class B seven-transmembrane G protein-coupled receptors that are activated by glucagon play a fundamental role in regulating blood glucose levels. These receptors, namely the glucagon receptor (GCGR) and the glucagon-like peptide 1 receptor (GLP-1R) also regulate insulin release from pancreatic beta cells and are currently major targets for developing new treatments and drugs for T2D. Glucagon binding elevates the second messenger cAMP through the activation of G proteins, and furthermore, the activated receptors are subjected to desensitization and internalization through recruitment of additional proteins, namely, GPCR kinases, ꞵ-arrestin and RAMPs. GLP-1R agonists enhance insulin secretion and reduce food intake, which promotes glucose lowering and reductions in body weight in patients with T2D. Glucagon agonists also increase satiety and induce energy expenditure, suggesting the combination of GCGR and GLP-1R agonism could have additive effects on weight reduction and further improve glycemia. Consequently, the GCGR is an emerging target in anti-diabetic therapy, particularly in the development of GCGR/GLP-1R co-agonists. However, there still remains an incomplete understanding of the signaling mechanisms invoked by either the GCGR or the GLP-1R, which limits the drug discovery to tackle T2D and associated morbidity. In this context, we have now identified that GCGR is subjected to ubiquitin-dependent regulation. Ubiquitin is a small protein that acts as a signaling code when appended to active protein complexes. Our data suggests that ubiquitination of the GCGR increases signaling through G proteins, whereas ligand binding causes de-ubiquitination, leading to decreased G protein coupling and increased ꞵ-arrestin binding and activity. There is limited information on the regulation of GLP-1R by ubiquitination. Thus, our studies will test the role of GCGR and GLP-1R ubiquitination in the propagation of signaling via these transducers and identify the molecular mechanism(s) that link ubiquitin-dependent signaling to cellular function.