The human innate immune response is an evolutionarily ancient first line of defense against invading bacterial and viral pathogens. This response consists of cellular and humoral elements, and it relies on receptors that recognize patterns of molecular structures on the surface of microorganisms that are absent from eukaryotic cells. Outcomes of recognition include induction of genes that encode antimicrobial peptides, initiation of an inflammatory response, and recruitment of cells involved in adaptive immunity. Comprehensive studies have revealed important age-dependent alterations that compromise the efficiency of the innate system and result in a baseline pro-inflammatory status, which is associated with increased risk of a wide range of diseases. Mechanisms of innate immunity are highly conserved across species, and Drosophila is an ideal model system for investigating the role of inflammatory processes on aging. A dramatic induction of the innate immune response-signified by increased expression of many NFkappaB dependent components of both the Imd and Toll pathways-has been documented in old flies. We hypothesize that the observed activation of NFkappaB signaling pathways is caused by endogenous, aging- related changes in the fly that generates a condition homologous to mammalian inflammation. This proposal focuses on the elucidation of these inflammatory-like changes, as they relate to aging, using primarily a genetic approach. It is planned to characterize the tissue-specific aspects of aging-related induction of inflammatory mediators in Drosophila and to determine if fly inflammation is a stochastic process or if it is regulated and associated with specific tissues. Tissues that are most susceptible to the effects of inflammation or that stimulate a systemic response will be identified, and candidate genetic pathways with established effects on aging will be tested with regard to their impact on aging-related inflammation. The data obtained from this work would serve to establish Drosophila as an important model system for the study of age-related inflammation and provide the basis for a future R01 application that is directed toward a more detailed analysis of candidate genetic mechanisms that may influence the process. ? ? ?
| Libert, Sergiy; Chao, Yufang; Zwiener, Jessica et al. (2008) Realized immune response is enhanced in long-lived puc and chico mutants but is unaffected by dietary restriction. Mol Immunol 45:810-7 |
