The physiological roles of PAPPA2

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The goal of my research is to understand the physiological and genetic factors underlying within-species variation in continuous traits such as body size. In previous work, I identified the PAPPA2 gene as potentially important for controlling variation in growth in mice. Little is known about PAPPA2, but a structurally related gene, PAPPA, is important in a variety of processes including pregnancy, bone development, cardiovascular disease, skin healing and aging. The goal of the proposed work is to improve our understanding of PAPPA2's function. I use mice as a model and have recently developed a resource that is unique to my lab: conditional PAPPA2 knock-out mice. A conditional knock-out is one in which it is possible to switch PAPPA2 off in certain tissues without affecting its normal function in other tissues. The specific questions I will address include: (A) Does PAPPA2 contribute to within-species variation in growth? Understanding the pathways through which variation in DNA leads to variation at the whole-animal level remains a major challenge in Biology. (B) Does PAPPA2 play a role in skeletal growth? Based on the biochemical action of PAPPA2, I predict that it is important for bone physiology. I will therefore switch off PAPPA2 in bone and measure effects on bone length and bone mineral density. (C) Does PAPPA2 play a role in placental development? PAPPA2 is highly expressed in the placenta, and recent studies have linked its expression to pregnancy complications in humans. I will examine whether switching off PAPPA2 in the placenta affects pregnancy outcomes such as birth weight and the incidence of prematurity. The proposed work will determine whether PAPPA2 might be useful for the diagnosis of certain medical conditions, as is the case with its close relative, PAPPA.