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Advancing Individualized Medicine by Understanding Phenotypic Integration Using the Human Skeleton as a Model System
Annual rept. 1 Sep 2010-31 Aug 2011
MOUNT SINAI MEDICAL CENTER OF THE CITY OF NEW YORK
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Susceptibility to common, heritable diseases is generally thought to originate at the genetic-level, and most studies seek genomic variants or altered molecular networks to develop novel diagnostics and treatments to reduce disease risk on a personalized basis. We show that fracture susceptibility in human tibiae and femora can also arise at a higher-level of biological organization, a phenomenon that may be difficult to predict from genetic information alone, because it involved biomechanical tradeoffs, constraints on cellular activity, and a network of compensatory trait interactions defining organ-level function. Importantly, we also identified a novel level of biological control regulating the degree of internal remodeling affecting young adult tibiae and aging femora. Limited compensation at this level of biological organization may be a public health concern, not only because of the increased fracture susceptibility, but also because it is unclear to what extent prophylactic treatments can circumvent intrinsic cellular constraints to establish a higher degree of functional equivalence among individuals. Thus, the funds supporting our research efforts have significantly advanced our understanding of bone by identifying a flaw or limitation in the functional adaptation process that may contribute to fracture risk and by discovering biological controls regulating internal remodeling that have not previously been reported.
APPROVED FOR PUBLIC RELEASE