In periodontitis, the consecutive tissues supporting the teeth are systematically destroyed by long term infections. Treatment, if successful, usually leads to repair by scarring as a result of the replacement of normal fibroblasts with granulation cells. Periodontal repair is not as advantageous to the patient as regeneration of a fully functional periodontium. In order to facilitate clinical regenerative therapies, we studied molecular and cellular mechanisms that control proliferation of distinct populations of normal and granulation fibroblasts cultured from human gingiva. These studies led us to scrutinize how the anti-microbial complement component C1q, which occurs in high quantities in normal and inflamed tissues, inhibits the growth of the host's cells. C1q acts as a stress activator. While normal fibroblasts respond to C1q by activating intracellular stress proteins associated with delays in cell select growth of granulation fibroblasts over normal fibroblasts, thus hampering periodontal regeneration. Verification of this hypotheses could provide a basis for more effective prevention and treatment of human periodontal disease through pharmacological and genetic manipulations of the affected tissues to enhance normal fibroblast function and regeneration of the periodontal apparatus. Specific goals are:
Aim I : To assess whether C1q modifies the growth response of the fibroblast populations by a block in cell cycle progression (cytostasis) or programmed cell death (apoptosis). Whereas cytostasis is reversible, apoptosis is irreversible. This information will provide a more predictable basis for evaluating the outcome of the disease on cellular composition, and therefore functionality, on the periodontium.
Aim II : To identify the molecular events that protect the granulation cells from C1q- induced stress, and use this information for future clinical applications aimed at improving the survival of normal fibroblast populations. Our strategy consists of characterizing C1q-induced stress pathways of normal fibr9oblast for identification of the biochemical steps activated by high levels of protein kinase A and by translocation of protein kinase C, which occurs in granulation cells only, in response to C1q. The methods for achieving these goals apply established pharmacological bioassays, histology, and flow cytometry techniques. This information will provide insights for the design of drugs that neutralize the detrimental effect of C1q upon the growth of normal fibroblasts, while retaining the beneficial antimicrobial activity of the complement cascade. While this work focuses on periodontitis, its results should be applicable to a variety of inflammatory diseases as well as wound healing.
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