COBRE Grant

The Cardiovascular Health Research Center at Sanford Research/USD receives funding through NCRR at the National Institutes of Health for a COBRE Project (P20RR017662).

Title: Mechanisms of Cardiovascular Remodeling
Principal Investigator: Dr. Alex Rabinovitch

Overview

The goal of this COBRE grant is to build a center of excellence in cardiovascular research at Sanford Research/USD. The original grant provided funding for 3 junior investigators with projects focused on ventricular remodeling in heart failure, for development of four research core laboratories, and the improvement of the research environment through recruitment of new faculty, purchase of equipment and funding of predoctoral fellows. The current COBRE grant provides support for five junior investigators with a continued focus on heart failure. The four core laboratories (Physiology, Cell Culture, Viral/Molecular biology, and Imaging) initiated in the original grant receive continued support as do programs for trainees (Pre- and Postdoctoral), and variety of seminar programs including science ethics, journal club research data integrity. Since 2002 COBRE support at Sanford Research/USD has resulted in 61 published manuscripts.
 

COBRE Investigators

Timothy O'Connell – The neurohormonal hypothesis, which suggests increased sympathetic nervous system activity is a causal factor in heart failure led to the standard use of b-adrenergic receptor antagonists in heart failure. However, clinical trials targeting sympathetic nervous activity and a1-adrenergic receptors indicated some adrenergic signaling might be beneficial. This was supported by recent work in our lab, where we showed a1-adrenergic receptors are required for adaptation to pathologic stress. COBRE project 1 tests the novel hypothesis that increased a1-adrenergic signaling will protect the heart from post-myocardial infarction remodeling.

Gregory Shearer – We have shown that vasoactive eicosanoids are transported in lipoproteins.  The role of these agents are well known, some as mediators of stable endothelial polarity and others as activators of NFκB-mediated inflammatory response, however their presence in lipoproteins could explain the vasoactivities associated of lipoproteins.  COBRE project 2 seeks to establish that lipoprotein-eicosanoids are a biologically important pool by synthesizing lipoproteins with customized eicosanoid profiles and measuring their impact on endothelial function.

Qiangrong Liang – Doxorubicin is a highly effective antitumor drug known to cause heart failure. COBRE project 3 is investigating how doxorubicin can cause heart failure and how to restore myocardial homeostasis by coordinately promoting survival mechanisms and blocking cell death pathways. We are especially interested in determining if abnormal activation of the ubiquitin proteasome system and autophagy, two cellular degradation pathways, contributes to doxorubicin cardiotoxicity. Specific treatment regimens have been identified that can enhance the anti-tumor efficacy of doxorubicin and at the same time attenuate its cardiotoxicity.

Erin Harmon – The goal COBRE Project 4 is to identify the function of human myotonic dystrophy protein kinase (DMPK) in myocyte development. DMPK was originally identified by the detection of a CTG triplet repeat sequence located in the 3’ untranslated region of the DMPK gene that is expanded in patients with myotonic dystrophy (DM1), but the consequence of reduced DMPK expression in DM1 is still unknown. Our work will lead to an understanding of DMPK function in myogenesis and will lay the groundwork for treatments for DM1 based on a complete understanding of DM1 myocyte pathophysiology.

Casey Wright – Clinical trials have shown that blockade of alpha-1 adrenergic receptor (a1-AR) activation can lead to increased incidence of heart failure in patients with hypertension and/or benign prostate hyperplasia. COBRE project 5 focuses on development of a new a1-AR antagonist for the treatment of hypertension and benign prostate hyperplasia. Current projects include localization of a1-AR subtypes in vascular and prostate smooth muscle cells versus cardiac myocytes and the signal transduction differences between a1-AR at the plasma membrane and a1-AR inside the cell.
 

COBRE Supported Core Facilities

Physiology Core – The Physiology core provides acquisition of ventricular functional data from small animal models of heart disease. Currently echocardiography and hemodynamic measurements are routinely performed.

Cell Culture Core – The Cell Culture Core provides primary cultures of adult mouse and neonatal rat cardiac myocytes and fibroblasts and will assist with primary cell culture needs for any tissue.

Viral/Molecular Biology Core – The Viral/Molecular Biology core provides high quality adenoviruses to laboratories for research use. Services include Construction of recombinant adenoviruses, and amplification, purification and tittering of adenoviruses.

Imaging Core – The Sanford Research Imaging Core utilizes light and confocal microscopy to visualize both living and fixed cells.  We are equipped with two confocal microscopes (Olympus FV1000 and FV300), capabilities for 4-color simultaneous imaging, Imaris image analysis software, and multiple light microscopes.