Proteomic-based mechanistic analysis of components involved in the immunoprotective pathways regulated by low-dose radiation and the medicinal mushroom Trametes versicolor
EMSL Project ID
25664
Abstract
The goal of this proposal is to identify molecular mechanisms that underlie radio-adaptive immune responses. We propose to use quantitative mass spectrometry to investigate the effects of radioprotective agents on pathways involved in macrophage activation. Promotion of cellular responses by these agents ultimately protects an organism from high-dose radiation damage. A detailed mechanistic understanding of this process would provide predictive capabilities for determining 1) human health risks associated with low level radiation exposures and environmental contaminants; and 2) patient responses to medicinal therapies used in conjunction with radiation treatments. Both low-dose radiation (10cGy or lower) and T. versicolor medicinal mushroom extracts provide protection from subsequent high-dose radiation damage. While both agents have been shown to enhance immune function, the molecular mechanisms of their immunoprotective effects are not well understood. We have shown that T. versicolor interacts with the LPS toll-like receptor 4 (TLR4) to enhance immune function, but known interactions with the complement receptor CR3 may also contribute to immunomodulatory actions. Adaptive effects associated with low-dose radiation are known to involve alterations in intracellular calcium levels, leading to the activation of calcium-dependent signaling proteins such as calmodulin (CaM). The role of CaM in activation of innate immune responses includes binding interactions with the transactivator protein NFkB and activation of inducible nitric oxide synthase (iNOS), both of which are involved in the TLR4 pathway. The similar modulatory effects on NFkB transcription regulation and enhancement of innate immune function induced by these radio-protective agents provide a comparative model to increase our mechanistic understanding of radio-adaptation. We propose to identify factors associated with radio-adaptive macrophage activation by low-dose radiation and T. versicolor-treated macrophages using mass spectrometry for the quantitative comparison of nuclear and cytosolic localization of proteins occurring upon treatment with these agents alone and in combination. The following hypotheses will be tested.1) Comparable molecular mechanisms exist for the radio-protective effects observed by both low-dose radiation and the mushroom T. versicolor.
2) T. versicolor modulates downstream effects of high-dose radiation leading to radiation protection.
The detailed understanding of the molecular mechanisms that result in radio-adaptation will provide predictive risk assessment capabilities for exposures to environmental and medicinal agents such as natural products and low-dose radiation.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2007-07-09
End Date
2009-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members