Inflamation-Gene Expression by Monocytes in Frailty

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DESCRIPTION(provided by applicant): Frail older adults are at increased risk for functional decline, falls, hospitalization, nursing home placement, and early mortality as compared to non-frail older adults. Emerging evidence suggests that inflammation, as marked by elevated levels of CRP and IL-6, is associated with frailty. However, little is known about the scope of, and the underlying mechanisms that contribute to, the activation of the inflammation system in frail older adults. Monocytes play pivotal roles in the activation and regulation of local and systemic inflammation, and investigating monocytic expression of genes encoding cytokine mediators and receptors can provide considerable insight into molecular mechanisms that underlie activation of the inflammation system in frailty. The short-term goal of this proposal is to establish initial preliminary data for specific modulations in inflammation-specific gene expression of isolated monocytes from frail older adults. The long-term goal of this project is to utilize these findings for the development of more in-depth etiologic and interventional studies of frailty. We hypothesize that frail older adults have significant alterations in constitutive and LPS-induced monocytic expression of genes encoding IL-6, TNF-alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra). The primary objectives of this proposal are to test this hypothesis and to further explore initial evidence for modulations in constitutive and LPS-induced monocytic expression of genes encoding 80 other cytokine mediators and cell surface molecules in the frailty syndrome. To accomplish these objectives, we propose an exploratory investigation (R21) into constitutive and LPS-induced monocytic expression of genes encoding 84 cytokine mediators and cell surface molecules in community-dwelling frail and non-frail older adults. A validated frailty-screening tool will be used to identify 15 age-, race-, and sex-matched pairs of frail and nonfrail older adults. Monocytes will be isolated and cultured in the presence and absence of LPS. Constitutive and LPS-induced monocytic gene expression will be evaluated and compared between frail and non-frail subjects, using a commercially available, inflammation-specific gene array containing cDNAs of IL-6, TNF-alpha, IL-1beta, IL-1ra, and 80 other cytokine mediators and cell surface molecules. Candidate genes with significant differences will be further evaluated by quantitative RT-PCR. This initial evaluation of the constitutive and LPS-induced monocytic expression of genes encoding IL-6, TNF-alpha, IL-1beta, IL-1ra will set the stage for more discerning mechanistic studies on monocytic production and regulation of these important cytokine mediators in frail older adults. This project will also explore initial evidence for modulations in constitutive and LPS-induced monocytic expression of genes encoding 80 other cytokine mediators and cell surface molecules in frail older adults. Therefore, It will serve as a hypothesis-generating project, and a basis for hypothesis refinement, that will open new pathways for future mechanistic and, potentially, interventional investigations of frailty in old age.