Periodontal disease among adult humans is a significant public health burden. It is strongly associated with the gram-negative bacterium, Porphyromonas gingivalis, yet bacteria alone do not explain population variance in the disease. There is a notable genetic component to both disease incidence and severity. Mouse models have proven extremely valuable in dissecting the pathobiology of various diseases. Modern molecular genetics, including quantitative trait locus (QTL) analysis, is a powerful tool for unraveling the genetic polymorphisms underlying various diseases in the mouse, including susceptibility and resistance to infectious diseases. Large portions of the murine genome are shared with the human genome, so that identification and localization of murine loci have facilitated discovery of their human counterparts. During the current support period, the Principal Investigator has developed a mouse model in which alveolar bone loss is reliably induced in mice by oral infection with P. gingivalis. In collaboration with Dr. Derry Roopenian of The Jackson Laboratory, knockout mice with various discrete immunodeficiencies have been used to identify several factors that contribute to bone loss. The Principal Investigator has also found that different strains of immunocompetent mice differ in their susceptibility to bone loss after oral infection. Through F1 crosses and backcross of these mice, we have initial evidence that susceptibility and resistance to P. gingivalis- induced alveolar bone loss are heritable traits. It is proposed to study the genetic basis for this susceptibility and resistance. First, the pathophysiological processes that coincide with bone loss in this mouse model will be further characterized and other phenotypic biomarkers will be developed that correlate with bone loss. Second, QTL analysis will then be used to identify chromosomal regions associated with susceptibility and resistance. Together these aims will provide a fuller description of the pathobiology of P. gingivalis-induced alveolar bone loss and will allow the Principal Investigator to map loci and alleles involved in susceptibility and resistance. Mouse strains developed in this investigation will be available for others to study. Knowledge of the genetics gained here has a high likelihood of contributing to the identification of candidate genes in humans.
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