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NCIRE-The Veterans Health Research Institute is the leading private nonprofit institute devoted to Veterans health research in the United States. Our mission is to advance Veterans health through research.

We support the work of some of the nation's foremost physicians and scientists at the San Francisco Veterans Affairs Medical Center, the premier biomedical research facility in the VA system. All have faculty appointments at the University of California, San Francisco, which has its own proud traditions of research and patient care. We also partner with the U.S. Department of Defense to support health research on behalf of our men and women in the Armed Forces.

Those who have served in uniform have given their best for their country. In return, we believe that they deserve nothing less than the best health care research we can provide.

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David Lovett, MD

Professor of Medicine and Chief, Nephrology Section, SFVAHCS

Our laboratory has primarily focused in recent years on an examination of the role of matrix metalloproteinase 2 in progressive cardiac and renal failure. These studies have included determinations of transcriptional regulatory networks, impact of promoter haplotypes on gene expression and generation of a series of transgenic mice to directly test the significance of MMP-2 expression on renal and cardiac disease. We have demonstrated that MMP-2 alone is sufficient to trigger the entire process of progressive renal disease seen in humans, including glomerulosclerosis, tubular atrophy and interstitial fibrosis without the requirement for superimposed injury. In the heart we have published a series of studies demonstrating that MMP-2 directly mediates cardiomyocyte apoptosis and contractile failure. More recently we have characterized (Lovett, et al., PLoS One 2012) a novel intracelllular isoform of MMP-2 that activates innate immunity. The isoform is generated by oxidative stress mediated activation of an alternative promoter in the first intron of the MMP-2 gene, thereby generating an intracellular, active N-terminal truncated enzyme. Transgenic mice expressing this isoform in the heart develop severe cardiomyocyte hypertrophy, inflammation and sytolic failure. Transgenic mice expressing this isoform in the kidney develop progressive tubular atrophy due to apoptosis. We are currently determining the extent of expression of this MMP-2 isoform in clinical specimens of cardiac and renal tissue using a combination of histochemical and epigenetic approaches. In addition, we are studying the epigenetic regulation of the MMP-2 intronic promoter using a novel series of transgenic reporter mice and epigenetic techniques. We believe that both isoforms of MMP-2 represent appealing therapeutic targets and we are currently developing antibody and siRNA-based strategies to selectively inhibit the MMP-2 isoforms in models of cardiac and renal disease.

To see Dr. Lovett on Pub Med, click here.