Research projects in our lab build on Dr. Conover's discovery of PAPP-A in the 1990s and more recently on our development of a PAPP-A knockout mouse model. Our work shows that PAPP-A plays a critical role in amplifying local IGF action during fetal development, vascular injury, bone formation, aging and age-related diseases, and some cancers.
Novel anabolic therapy for osteoporosis using IGFs
An important goal in our lab is the ability to stimulate new bone formation and increase bone mass in osteoporosis. People with a rare syndrome of hepatitis C-associated osteosclerosis (HCAO) who develop marked increases in bone mass as adults first provided clues for an innovative approach using the IGF system.
The IGFs are important skeletal growth factors. Our detailed analysis of the IGF system in people with HCAO indicated a unique increase in an IGF-II precursor molecule and IGFBP-2. Subsequent studies in cultured human bones demonstrated preferential binding of the IGF-II/IGFBP-2 complex to bone matrix and stimulation of osteoblast proliferation. Animal studies showed increases in bone mineral density after short-term IGF-II/IGFBP-2 administration. We're continuing preclinical analyses of this novel anabolic approach to treat osteoporosis.
A recent study showed similar unique increases in an IGF-II variant, suggesting IGF-II may account for the preservation of bone mass during bear hibernation.
PAPP-A and aging
Diverse species with specific mutations in IGF signal transduction have enhanced resistance to oxidative stress and extended life spans. Our overall hypothesis is that the aging process can be regulated by PAPP-A, which degrades inhibitory IGFBP-4, thereby increasing IGF-I bioavailability. The corollary is that PAPP-A deficiency would result in increased longevity by decreasing IGF availability and receptor signaling.
We found that PAPP-A knockout mice live 30% to 40% longer than do their wild-type littermates. We're determining the physiological mechanisms underlying the life span extension by critically assessing the contribution of prenatal programming, metabolism, resistance to oxidative stress, preservation of immune competence and prevention of tumor growth. We have the models and the technology to enable us to make significant contributions to the understanding of PAPP-A and the IGF system in the fundamental biology of aging, with implications for novel strategies to slow the aging process and enhance longevity.
PAPP-A and atherosclerosis
Using specific monoclonal antibodies, we identified abundant staining for PAPP-A in eroded and ruptured plaques from human arterial specimens. The most intense staining for PAPP-A was at the inflammatory shoulder of the ruptured plaques containing smooth muscle cells and activated macrophages. There was little or no staining for PAPP-A in stable plaques.
Our overall hypothesis is that PAPP-A is a key regulatory factor in the vascular response to injury leading to atherosclerosis and promoting plaque vulnerability.
We're conducting experiments to determine the underlying mechanisms for elevated PAPP-A in vulnerable plaque using human tissue and cell models. In addition, we're determining the effect of PAPP-A deficiency and of targeted PAPP-A overexpression on the development and progression of atherosclerotic plaque in mice on an apolipoprotein E-null background.
This project seeks to gain a better understanding of PAPP-A and the IGF system in the fundamental biology of cardiovascular disease and should establish PAPP-A as a therapeutic target in atherosclerosis.
PAPP-A and pulmonary fibrosis
Our lab is studying the role of PAPP-A in progression of fibrosis using adult human lung fibroblasts in vitro and a lung injury model in mice in vivo.
PAPP-A and Alzheimer's disease
We're starting a study to examine the effect of PAPP-A gene deletion on brain pathology and cognitive changes in a mouse model of Alzheimer's disease.