Five $50,000 seed grants were awarded in 2010 addressing the question: How does the cardiovascular system age?
1. Comprehensive and real time assessment of a genetic risk score for cardiovascular disease in the Women's Health Initiative
PI: T. Assimes Collaborators: John Ioannidis, Marcia Stefanick, Manisha Desai, Josh Knowles and Marco Perez. Recent advances in genetics have facilitated the identification of susceptibility loci for coronary atherosclerosis and its risk factors. Here, we propose to use the rich bio-resource formed by the Women’s Health Initiative to develop an infrastructure that will comprehensively and in real time assess the utility of a multi-locus genetic risk score (GRS) for CAD in women ≥50 years of age. Importantly, the make-up of this bio-resource will provide us with enough power to test the modifying effect of age on GRS. The results of this study will provide the scientific community with valuable insights into the pathophysiology of early vs. late onset atherosclerosis disease in women as well as differences in the pathophysiology between men and women. The results will also allow the scientific community to gauge the appropriate time to conduct key large-scale clinical trials to prove the utility of GRS in women.
2. Effects of Aging and Gender on Abdominal Aortic Aneurysm Development, and the Role of MicroRNAs
PI: J. Spin Collaborators: Junya Azuma, Alicia Deng, Lars Maegdefessel, Philip S. Tsao, Atul Butte, Alex A. Morgan Aging leads to both dilatation and substantial stiffening of the aorta, and constitutes one of the primary risk factors for the development of abdominal aortic aneurysm (AAA), a major source of morbidity and mortality. Using a mouse model of AAA, we propose to study gene expression changes associated with aging and gender, consisting of both mRNA and miRNA profiling of aortic segments. We will develop analysis methods to identify age- and gender-related regulatory gene modules and key miRNA master regulators, which will be tested for disease-modifying therapeutic potential in future studies.
3. Nanoscale in situ force measurements to uncover the roles of mechanical force in age-associated ventricular hypertrophy
PI: A. Dunn Recent observations suggest that molecule-level mechanical forces between cells are critical in governing age-related cardiac tissue remodeling. Current techniques for measuring the forces experienced by cells are ill suited for use with three-dimensional cellular assemblies, and are wholly incompatible with in vivo measurements. We will develop a new fluorescence microscopy technique, termed molecular force microscopy (MFM), that directly visualizes the mechanical forces experienced cells in culture, and eventually in whole organisms. We will use MFM to measure, with millisecond and micrometer accuracy, the fluctuating mechanical forces experienced by cardiomyocytes working against externally applied strain. These measurements will test the working hypothesis that pathological ventricular hypertrophy is the direct result of chronic mechanical stress experienced by cardiomyocytes.
4. Telomere Biology & Cardiovascular Aging in Healthy Volunteers
PI: F. Haddad, Co-PIS: S Shen-Orr, C Weyand, M. Davis, Collaborators: Ingela Schnittger, D Liang, .J Montoya, A Butte, M.D. Ph.D. Cardiovascular aging is often associated with progressive atherosclerosis, increased arterial stiffness, impaired ventricular filling and decreased maximal cardiac output with exercise. Studies have shown that several differences in cardiovascular aging exist between men and women and vary according to fitness level. Recent data also suggests that cellular aging reflected by leukocyte telomere length is associated with atherosclerosis and cardiovascular disease risk. Telomere length serves as a marker of replicative immunosenescence. At this time, the relationship between cardiovascular aging and immune aging (also known as immunosenescence) has not been explored in depth. Here, we propose to analyze the relationship between cardiovascular aging, telomere biology and immunosenescence using novel integrative analysis methods. As part of the project, we will also determine cardiovascular aging profiles according to sex and level of activity in a cohort of 300 healthy volunteers.
5. Novel metabolic imaging of age-related redox changes and cardiomyopathy in Duchenne's Muscular Dystrophy
PI: H. Blau Collaborators: F Blankenburg, F Mourkioti, s Sampath, S Sampath, M McConnell Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder of children, is characterized by continuous injury and progressive degeneration of skeletal and cardiac muscle, and uniformly leads to death from cardiomyopathy and/or diaphragmatic failure. While the molecular mechanism linking dystrophin mutation to cardiac failure remains unclear, altered redox homeostasis has been suggested to play a critical role. In a new cross-departmental collaboration, we have preliminary data describing a novel method for metabolic imaging of the heart, which allows direct readout of the age-related perturbation of redox homeostasis known to occur in DMD. Using a new and clinically relevant mouse model of DMD developed in the Blau lab (Sacco et al 2010, Cell, in press), we have strongly validated this strategy, demonstrating profound cardiac redox abnormalities in aging dystrophic animals, as revealed using non-invasive molecular imaging. Critically, these imaging findings are apparent before symptoms become evident clinically or by echocardiography, providing new insight into and mechanisms for the study of age-related dysfunction in the heart. Seed funding will allow us to develop this imaging reagent in our preclinical model, advance it towards clinical use in DMD patients, and allow us to establish its utility in other forms of cardiomyopathy, including in ischemic disease.
