CD14 is a 55 kDa glycosyl phosphatidylinositol-linked protein that is also present in a soluble form in serum. CD14 binds lipopolysaccharides (LPSs) derived from the outermost layer of Gram-negative bacteria and activates a signaling cascade that results in the production of inflammatory cytokines that include tumor necrosis factor alpha, interleukin-6, and interleukin-1. This response has been shown to be important in the pathogenesis of septic shock following Gram- negative septicemia. Recent data have also suggested that a similar response may play a role in accelerating atherosclerotic plaque development and in enhancing the formation of the macrophage foam cell, the histologic hallmark of the early atheroma. Several lines of evidence also implicate this pathway in the pathogenesis of PID, a leading cause of infertility in the developed world, and in the phagocytosis of apoptotic cells, an essential event in tissue remodeling and development. Investigators working on inflammatory bowel disease, periodontal disease, and a variety of inflammatory pulmonary disorders have also postulated an important role for CD14 in these conditions. Given the widespread interest in understanding the contributions of CD14 to normal physiology and pathologic conditions, the applicant's laboratory has generated homologous recombinant mice lacking this protein. This grant application proposes to generate a breeding colony of these animals and to distribute these mice to the many investigators that have requested them. These investigators, working on diseases supported by a diverse group of NIH Institutes, can then utilize these animals in experiments that explore the biological processes in which CD14 activity has been implicated. In addition to developing the breeding colony of CD14 deficient mice, this application proposes to characterize the utility of these animals as models for diseases that represent major human health problems in which the principal investigators of the grant have established research efforts. Thus, the CD14 deficient animals will be bred into mouse strains that are susceptible to atherosclerosis in order to explore the role of Chlamydial infections in the pathogenesis of cardiovascular disease. In addition, CD14-null mice will also be used to explore the role of the endotoxin signaling pathway in mouse models of PID. This work is intended to broaden the applicability of CD14 deficient mice to research involving acute and chronic inflammatory disease and to make a critical animal resource available to the investigative community at large.
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