Project Details
Description
The impact of nutrients and nutrient-derived metabolites on bone metabolism is an underexplored area. An age-
associated increase in the generation of toxic reactive oxygen species has been implicated in osteoporotic
disease, and our central hypothesis is that nutrient-derived oxidation products in particular play a key pathogenic
role. Our previous data demonstrate that the tryptophan breakdown product, kynurenine, acting through the aryl
hydrocarbon receptor, has detrimental effects on bone mass. This metabolism of tryptophan to produce
kynurenine is mediated by the enzyme indoleamine 2,3-dioxygenase (IDO), which can be induced by interferon
and regulates the immune system. However, not all of the metabolites generated from IDO-mediated tryptophan
breakdown are detrimental (e.g., NAD+, melatonin, and picolinic acid may be beneficial). Our goal is to
characterize the physiologic effects of tissue-specific blockade of the IDO pathway and then to determine
whether selective re-addition of specific tryptophan metabolites maximizes gains in bone mass. To accomplish
these goals, we propose the following specific aims: (1) Test the hypothesis that tissue-specific knockout of IDO1
will prevent inflammation-related bone loss; and (2) Test the hypothesis that different tryptophan metabolites are
predominantly anabolic or catabolic. This project will also synergize with the other projects included in this
application looking at effects of these metabolites in aging muscle (Project 2), mitochondrial function and cell
senescence (Project 3) and in terms of sex-specific effects (Project 4). These innovative studies, together with
the other tightly integrated projects of the Program Project proposal should provide new therapeutic targets for
improving musculoskeletal health and increasing healthspan.
Status | Active |
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Effective start/end date | 6/1/23 → 5/31/24 |
Funding
- National Institute on Aging: $315,700.00
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