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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES033533&format=word)
| Principal Investigator: Holian, Andrij | |
|---|---|
| Institute Receiving Award | University Of Montana |
| Location | Missoula, MT |
| Grant Number | R01ES033533 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 05 May 2022 to 31 Mar 2027 |
| DESCRIPTION (provided by applicant): | Lung and systemic diseases as a result of micron-sized particle exposures (e.g., silica, asbestos, and more recently, dusts from preparation of granite countertops) are a critical health problem in the US and around the world. Unfortunately, these diseases remain untreatable in part due to lack of information on the mechanisms of injury and inflammation. To date, extensive research that has failed to identify the key steps with potential for therapeutic intervention. Adding to the potential problems of the above particle exposures, there are growing concerns that the increased use of engineered nanomaterials (ENM) will add to the burden of lung and systemic diseases in humans exposed in environmental and occupational settings to these new materials. We know that the physicochemical characteristics of ENM play a role in toxicity and hazard potential. Therefore, there is a critical need to understand how specific physicochemical properties of ENM (e.g., surface chemistry, charge and wettability) affect cell function and in vivo inflammatory outcomes. Furthermore, although MeO ENM have been shown to cause inflammation, leading to lung fibrosis, the precise mechanisms of ENM-induced inflammation remain unclear. We have demonstrated that ENM cause phagolysosomal membrane permeability (LMP), leading to release of lysosomal proteases, which have been implicated in downstream effects such as NLRP3 inflammasome activation, and mitochondrial damage in alveolar macrophages, and significantly contribute to in vivo inflammation and pathology. However, the mechanisms responsible for LMP, which we proposed to be the key rate-limiting effect of ENM and silica toxicity, remain unknown. This uncertainty impedes the progress in the field of particle-induced inflammation and nanotoxicology and limits the ability to develop targeted treatments for adverse health effects. Our central hypothesis is that the relative biological activity of ENM and silica is dependent on specific surface properties that define particle-phagolysosome membrane interactions leading to LMP. Furthermore, we postulate that ENM and silica interact with the interior of the phagolysosomal membrane leading to K+ flux through the BK channel and membrane hyperpolarization causing LMP and initiate the inflammatory pathway described in our model. The following aims will test our central hypothesis and accomplish our goals: 1: Synthesize and characterize MeO ENM with specific physicochemical properties.; 2: Determine the mechanism of MeO-induced LMP leading to toxicity and NLRP3 inflammasome activation and the relationship between ENM surface properties and biological activity; and 3: Demonstrate that in vitro MeO ENM-induced LMP and macrophage responses define in vivo pathology following aerosol exposures to selected MeO ENM. It is anticipated that these studies will help elucidate the primary mechanism responsible for MeO ENM-mediated LMP, confirm the central role of LMP in macrophage response to ENM as well as in inflammation and pathology and test potential therapeutics. |
| Science Code(s)/Area of Science(s) |
Primary: 78 - Nanotoxicology Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | See publications associated with this Grant. |
| Program Officer | Srikanth Nadadur |