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POSTDOCTORAL FELLOWSHIP.
Prolonged spaceflight causes osteopenia due to decreased bone formation secondary to impaired osteoblast proliferation and increased osteoblast apoptosis. Hindlimb unloading by tail suspension, a model for skeletal unloading of spaceflight, causes osteoblast precursor and skeletal tissue resistance to the effects of insulin-like growth factor-1 (IGF-1). The nature of this resistance is characterized by decreased activation of the IGF-1 receptor and downstream signaling pathways. Osteoblast precursors from unloaded bones demonstrate decreased expression of integrins, and treatment of normal osteoblasts with echistatin, an integrin antagonist, recreates the phenomena of unloading-induced IGF-1 resistance. Additionally, mechanical stimulation of human osteoblasts activates the IGF-1 receptor and augments the receptor response to IGF-1. These effects are abrogated by echistatin treatment. These findings suggest that integrin receptors have a role in the regulation of IGF-1 receptor in osteoblasts.
Our hypothesis is that interaction of integrin and IGF-1 receptor signaling cascades is required for IGF-1 activation of its receptor and intact IGF-1 signaling in osteoblasts. Mechanical loading stimulates the formation of an integrin/IGF-1 receptor complex, thus, enhancing IGF-1 signaling and enabling mechanically induced osteoblast proliferation and bone formation. To test the hypothesis, we propose the following specific aims:
1. Determine the means by which skeletal reloading regulates skeletal response to IGF-1. Tail suspended rats treated with IGF-1 will be skeletally reloaded to preserve bone mass and osteoblast IGF-1 signaling. Integrity of IGF-1 signaling will be correlated with the interaction between integrins and the IGF-1 receptor.
2. Determine the mechanism for regulation of the osteoblast IGF-1 receptor by integrins in response to mechanical loading by pulsatile fluid flow. Formation of the integrin and IGF-1 receptor complex in human osteoblasts will be stimulated by fluid flow loading in order to determine the components within the complex and their function.
The feasibility of intermittent reloading and IGF-1 infusion to prevent unloading-induced bone loss will be established. Furthermore, establishing the interaction between integrins and the IGF-1 signaling cascade in osteoblasts will provide potential targets for countermeasure treatments to preserve the effects of mechanical loading and prevent the bone loss of spaceflight. |