2006 CVI Seed Grants Recipients
Stanford Cardiovascular Institute Seed Grants Yield Novel Translational Research
Feb 3,2006 - The Stanford Cardiovsacular Institute awarded $250,000 in five seed grants of $50,00 each to fund unique interdisciplinary collaborations of CVI members.
"The Cardiovascular Institute’s research seed grants advance the integration of Stanford’s rich array of multidisciplinary cardiovascular research to achieve the Institute goal: to improve diagnosis, treatment, prevention and ultimately to eliminate heart and vessel disease," said Dr. Robbins. "The proposals were of such high quality, another nine received "Honorable Mention." The five seed grant projects are described below:
Investigator: Joseph Wu, MD, PhD
Cardiology and Radiology
Collaborators: Irving Weissman, Cancer and Stem Cell Institute, Dr. Sanjiv Gambhir, Molecular Imaging Program at Stanford, Tom Quertermous, Cardiology and Genomics, Andrew Connolly, Pathology, and Phillip Yang, Cardiac MRI).
Improving Cardiac Repair by Stem Cell Mediated Gene Therapy
This project is studying novel therapeutic aspects of combined stem cell and gene therapy for treatment of ischemic heart disease. Genetic modification of stem cells may represent an important strategic advancement in regenerative medicine for heart repair. The collaboration has already resulted in a publication focusing on the survival, proliferation, and migration of embryonic stem cells after transplantation in the myocardium.
PET/CT imaging of myocardial viability. A healthy human subject underwent a combined [18F]-FDG PET/CT scan to assess myocardial viability. The transverse PET image (left) shows significant LV uptake of the [18F]-FDG tracer (hypointense signal). The transverse CT image (middle) delineates the boundaries of the whole heart in the chest cavity. Co-registered PET/CT fusion image (right) confirms the strong uptake of [18F]-FDG to be in the LV myocardium.
Investigators: Tom Quertermous, MD, and Philip Tsao, PhD
Cardiology and Genetic Epidemiology
Collaborators: Tim Assimes, cardiology and disease prevention; Stephen Fortmann, Center for Research in Disease Prevention, classical epidemiology and cost effectiveness; Mark Hlatky, Health Research and Policy, human genetics; Rick Myers, Genetics and Human Genome Center and biostatistics; Richard Olshen. Other external collaborators are Drs. Carlos Irbibarren, Alan Go, and Neil Risch (Kaiser Permanente and/or UCSF) as well as Dr. Dan Levy (Framingham Heart Study).
Genetic Determinants of Coronary Artery Disease
Coronary artery disease (CAD) is a inflammatory disease driven by the response to vascular injury and characterized by endothelial dysfunction. Even in the presence of traditional risk factors, the progression of CAD is highly variable. Traditional risk factors explain only about 30% of the variation in the risk of CAD. The heritability of atherosclerosis (the proportion of the disease variance not explained by traditional genetic risk factors is estimated at 40%. Understanding of the genes and mutations involved is limited. To identify novel genetic modifiers of CAD is the objective of this multidisciplinary collaboration
Investigator: Euan Ashley, MRCP, PhD
Collaborators: Kavita Ernst, Daniel Bernstein, Randall Vagelos, Michael Fowler, Thomas Quertermous, Pediatric and Adult Cardiovascular Medicine.
Apelin in Human Heart Failure
Heart failure is a leading cause of hospitalization and the most costly cardiovascular disorder in the United States. Despite its enormous human and economic burden, there is little consensus as to the optimum treatment for decompensated function. Further, longstanding concerns over increased mortality associated with inotropic agents, combined with newer concerns over the consequences of traditional diuretics and more recently approved agents such as nesiritide leave few options for the evidence-based care of this group of patients. New approaches which target upstream of traditional agents are urgently required.
In 2003, we demonstrated the importance of a novel neurohumoral pathway in human heart failure. Specifically, transcription profiling of human left ventricles ( LV) revealed that expression of the G protein coupled APJ receptor was more significantly upregulated than any other gene following offloading with a left ventricular assist device. We went on to localize the receptor and its recently discovered ligand, apelin, through the development of antibodies to both, develop an immunoassay kit for the measurement of tissue and protein levels, characterize both acute and hemodynamic consequences to apelin infusion, knock out the apelin gene, and assay plasma levels of apelin in cohorts of heart failure patients. Translation of this promising agent to clinical trials is now timely.
Investigator: Oscar Abilez, MD
Collaborators: Cheng pei Xu MD, PhD, Chris K Zarins MD , Philip Tsao PhD, Charles Taylor PhD.
Genomic, Morphometric, Hemodynamic, and Mechanical Investigation of Rat Arteries in a Pulsatile Organ-Culture System
The goals of the study are to establish an organ culture system that would sustain harvested arteries under physiologic conditions and pulsatile flow. The proposed study would provide realistic, yet discrete, biological inputs into a cultured arterial system. The arterial specimen is subjected to constant, pulsatile, laminar and turbulent flows. The artery can be studied en bloc or in small segments. Histology, morphometry, immuno-staining, RNA and protein expression along with establishment of rigorous flow dynamics will provide invaluable clues into development of arterial pathology, in specific atherorsclerosis and intimal hyperplasia.
Preliminary gene profiling results indicate immediate expression of various genes. Using techniques in gene mapping, and transcription one can trace the pathologic process to its molecular mechanism(s). In addition, correlating gene expression to the introduced physical/chemical variable may pinpoint specific stimuli that trigger arterial disease. With the genomic and hemodynamic data at hand, drugs may be designed to block one or more of the pathways, arresting the disease process. Collaborators are from the Division of Vascular Surgery, Department of Cardiovascular Medicine and Department of Biomechanical Engineering
Investigator: Daniel Bernstein, MD
Collaborators: David Rosenthal, Michael Fowler, Euan Ashley, George Van Hare, Paul Wang, Anne Dubin, Department of Pediatrics/Cardiology and Department of Medicine/Cardiovascular Medicine
Cardiovascular Genomics/Proteomics Program and Core Facility
Great progress has been made in the hypertrophic cardiomyopathies in identifying the genetic origin of cardiovascular disease. Mutations in at least ten different genes have been implicated, all of which encode protein components of the cardiac sarcomere, either components of the thick or thin fibers or associated regulatory subunits. Mutations of the cardiac ß-myosin heavy-chain gene (chromosome 14q1) and the myosin-binding protein C gene (chromosome 11q11) are the most common. Over 200 mutations have been identified in the ten most common genes; many patients carry more than one mutation.
Progress has also been made in identifying the genetic basis of dilated cardiomyopathy, which is now recognized to be familial in 20-50% of cases. Autosomal dominant inheritance is most commonly encountered and, to date, at least 16 genes have been identified. X-linked inheritance accounts for 5- 10% of cases of familial dilated cardiomyopathy. Similar advances have been made in the genetics of ventricular arrhythmias, some forms of congenital heart block, understanding the genetic basis of heritable arrhythmias and the role of single nucleotide polymorphisms (SNPs) in determining the outcome of patients with heart failure.
Besides offering the potential of genetic counseling for family members of the index patient, accumulating data suggest that genotype may be helpful in predicting clinical outcome for many genetically based cardiovascular disorders, e.g. risk of sudden death in patients with hypertrophic cardiomyopathy.
This project advances the Stanford Cardiovascular Institute’s goals 1) to foster further collaboration between clinicians and basic scientists, as well as between adult and pediatric clinical services, 2) to recruit a part-time cardiovascular genetics consultant to further development of a translational research program, and 3) to assist in development of the genomics/proteomics core. of samples for future genomics/proteomics studies.