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This is an application for an Independent Scientist Award (ISA) K02. The applicant is a very productive, experienced, and NIH- funded investigator. Her research focuses on cytokine signal transduction in osteoblastic cells and its effects on bone remodeling. The applicant works in a rich and productive environment provided by the Center for Osteoporosis and Metabolic Bone Diseases at the University of Arkansas for Med. Sciences. Her work as an independent investigator demonstrated that osteoblastic cells display receptors for IL-6 type cytokines (IL- 6, IL-11, LIF, CNTF, and OSM); that receptor activation induces differentiation and prevents apoptosis of osteoblastic cells; and that, in an osteoblastic cell line, cytokine effects require the transcriptional activation of the cyclin dependent kinase inhibitor p21WAF1, SDI1, CIP1. In addition, cells representing different stages of differentiation express different receptor repertoire, and receptor expression is modulated by systemic hormones. Based on this, she proposes the following interrelated working hypotheses: IL-6 type cytokines promote differentiation and prevent apoptosis of osteoblastic cells by regulating the expression of p21WAF1, SDI1, CIP1. Different receptor repertoires are expressed at different stages of osteoblast differentiation in vivo, and systemic hormones influence the differentiating and anti-apoptotic effects of the cytokines by modulating receptor expression. To test these hypotheses, she proposes to: 1) Investigate the mechanism of the anti-apoptotic effect of the cytokines using MG-63 osteoblastic cells and p21 deficient osteoblasts, and transfections with dominant negative and constitutively or inducibly active molecules of the cytokine signaling pathway. 2) Determine the effects of systemic hormones on receptor expression; and examine whether these changes alter cell responses to the cytokines. And, 3) Determine the pattern of distribution of cytokine receptors in osteoblastic cells in vivo, in murine bone marrow cell aspirates and sections of undecalcified bone from mice, by in situ RT-PCR in combination with histostaining and dynamic bone histomorphometry. The K02 award will permit the applicant to focus her research on cytokine signaling in bone and to enhance her cell/molecular biology skills, as the immediate goals; and to achieve scientific maturity in a uniquely strong environment as her academic career progresses.

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