Cheryl A. Conover, Ph.D., has been investigating the insulin-like growth factor (IGF) system for 30 years.
The IGFs are peptide growth factors, structurally related to insulin, that are important regulators of growth and differentiation in various tissues and cell systems. The actions of the IGFs are, in turn, determined by a family of IGF binding proteins.
Furthermore, her laboratory team discovered a novel enzyme (called PAPP-A) that enhances IGF activity by degrading inhibitory IGF binding proteins. Ongoing studies in the laboratory use methodologies of cell biology, protein biochemistry, immunohistochemistry and molecular biology, as well as microsurgical techniques with genetically engineered mouse models.
In particular, Dr. Conover took a sabbatical in the laboratory of Jan van Deursen, Ph.D., at Mayo Clinic and generated a mouse with the PAPP-A gene deleted. These PAPP-A knockout (KO) mice have proven to be very valuable animal models, especially for the study of PAPP-A and IGFs in aging and age-related disease.
Dr. Conover's research has been funded by the National Institutes of Health, the American Heart Association and the Ellison Medical Foundation for Aging Research, among other organizations.
- PAPP-A as a new marker for acute coronary syndrome. In collaboration with colleagues in the Division of Cardiovascular Diseases at Mayo Clinic, Dr. Conover published a paper in the New England Journal of Medicine in 2001 indicating that circulating PAPP-A in humans may be a new marker for acute coronary syndromes, with elevation in levels associated with enhanced risk for heart attacks.
This observation has been borne out in clinical studies by several groups at Mayo and around the world, and PAPP-A assays are now being incorporated in major trials assessing cardiac biomarkers.
- PAPP-A and cardiovascular disease. Since human atherosclerotic and restenotic vascular lesions express high levels of PAPP-A, Dr. Conover hypothesized that in the absence of PAPP-A, lesion development would be attenuated.
This hypothesis was first tested in an injury-induced model of stenosis of the carotid. Wild-type mice exhibited progressive stenosis resulting in near occlusion of the carotid lumen, whereas PAPP-A KO mice were completely resistant to lumen narrowing.
Similarly, atherosclerotic plaque development was inhibited by 80 percent in PAPP-A KO mice fed a high-fat diet compared with wild-type mice. Conversely, mice overexpressing PAPP-A in arteries had enhanced atherosclerotic lesion development.
Therefore, PAPP-A may not only be a marker of "vulnerable" plaque, but also a therapeutic target for atherosclerosis. These studies are ongoing.
- PAPP-A and aging. PAPP-A KO mice live 30 to 40 percent longer than their wild-type littermates, with reduced incidence and delayed occurrence of spontaneous cancers and degenerative disease. Dr. Conover's team is examining the molecular mechanisms underlying the extended healthy longevity of PAPP-A KO mice.
- PAPP-A and adipose tissue. New studies have been started to investigate the role of PAPP-A in the different fat depots of mice and men, based on initial findings that PAPP-A is preferentially expressed in visceral fat.
- PAPP-A and cancer. Overexpression of PAPP-A in a relatively non-tumorigenic ovarian cancer cell line markedly increased tumor growth in nude mice. Dr. Conover's lab is currently testing inhibitors of PAPP-A for their ability to suppress tumor growth.
Significance to patient care
Further validation of PAPP-A levels in blood as a biomarker of acute coronary syndromes would introduce a new noninvasive test to identify patients at risk for a heart attack. PAPP-A may also be a therapeutic target for atherosclerosis, visceral obesity and some cancers.
- George M. and Edna B. Endicott Professor of Medicine, Mayo Clinic, 2002-present
- Chair, Institutional Animal Care and Use Committee, Mayo Clinic, 2004-2008
- Chair, Gordon Research Conference on "Insulin-like Growth Factors in Physiology and Disease", 2005-2007
- Director's Award for Outstanding Contributions to Aging Research, Robert and Arlene Kogod Center on Aging, Mayo Clinic, 2011
- Associate Editor, American Journal of Physiology: Endocrinology and Metabolism, 2010-present
- Supervising Editor, Aging Cell, 2011-present