SUMMARY
The research of Cheryl A. Conover, Ph.D., has been investigating the insulin-like growth factor (IGF) system for 30 years.
IGFs are peptide growth factors, structurally related to insulin, which 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.
Her laboratory team discovered a novel enzyme called pregnancy-associated plasma protein-A (PAPP-A) that enhances IGF activity by degrading inhibitory IGF binding proteins. Ongoing studies in the laboratory use methods of cell biology, protein biochemistry, immunohistochemistry and microsurgical techniques with genetically engineered mouse models.
Dr. Conover generated a mouse with the PAPP-A gene deleted. These PAPP-A knockout (KO) mice are long-lived and resistant to degenerative diseases of aging. They have proved to be valuable animal models for the study of PAPP-A and IGFs in aging and age-related disease.
Dr. Conover's research is funded by the National Institutes of Health, the American Heart Association and the Ellison Medical Foundation for Aging Research, among other organizations.
Focus areas
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 reduced.
This hypothesis was first evaluated in an injury-induced model of narrowing 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% 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.
- PAPP-A and aging. PAPP-A KO mice live 30% to 40% longer than their wild-type littermates, with reduced incidence and delayed occurrence of spontaneous cancers and degenerative diseases. Dr. Conover's team is examining the molecular mechanisms underlying the extended healthy longevity of PAPP-A KO mice.
- PAPP-A and adipose tissue. Several of Dr. Conover's studies investigate the role of PAPP-A in the different fat depots of mice and humans. She found that PAPP-A is preferentially expressed in visceral fat. Deletion of the PAPP-A gene or treatment with a monoclonal antibody inhibitor of PAPP-A's proteolytic activity selectively prevents the development of visceral obesity in mice.
- PAPP-A and cancer. Overexpression of PAPP-A in a relatively nontumorigenic ovarian cancer cell line markedly increased tumor growth in nude mice. On the other hand, inhibition of PAPP-A in ovarian tumor grafts reduced tumor growth and ascites buildup.
- PAPP-A and age-related diseases. Studies from Dr. Conover's lab show that genetic and pharmacological inhibition of PAPP-A have beneficial effects on diabetic nephropathy, polycystic kidney disease, pulmonary fibrosis, thymic involution and sarcopenia.
Significance to patient care
PAPP-A is a promising target for healthy aging.
Professional highlights
- Review editor, Frontiers in Endocrinology, 2023-present.
- Supervising editor, Aging Biology, 2023-present.
- Metabolism section editor, Experimental Gerontology, 2019-present.
- Associate editor, Growth Hormone and IGF Research, 2015-present.
- George M. and Edna B. Endicott Professor of Medicine, Mayo Clinic, 2002-present.
- Supervising editor, Aging Cell, 2011-2022.
- Honorary doctorate, Aalborg University, Denmark, 2019.
- Fellow, American Aging Association, 2018.
- Director's Award for Outstanding Contributions to Aging Research, Robert and Arlene Kogod Center on Aging, Mayo Clinic, 2011.
- VELUX Visiting Professor, Aalborg University, Denmark, 2011.
- 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.