Project Summary/Abstract: Combustion of wood and other forms of biomass releases enormous quantities of toxic materials into the air and is linked to multiple human morbidities and an estimated 3-4M excess deaths/year. Like many forms of particulate materials (PM), wood/biomass smoke PM (WBSPM) is pneumotoxic. WBSPM exposure increases people's susceptibility to respiratory infections, exacerbates asthma, and causes emphysema and COPD. Exposure to WBSPM is often unavoidable even in modern society and specific molecular and chemical interactions that link exposure to the established acute and long term effects of WBSPM are not fully understood. Accordingly, the ability to treat respiratory and other conditions resulting from exposure to WBSPM, and ways to effectively reduce risks to humans, are extremely limited. We propose a novel mechanistic paradigm for how WBSPM can cause deleterious effects in the lungs, through activation of the Ca++ ion channel transient receptor potential vanilloid-3 (TRPV3). Our data show that WBSPM activates TRPV3. Assessment of the proposed TRPV3-dependent mechanistic paradigm will provide fundamental data to potentially predict human risks for respiratory conditions associated with WBSPM exposure by establishing new mechanisms for toxicity. In doing so, this study has the potential to reveal innovative approaches to discover interventions for the prevention and treatment of such diseases, and perhaps more broadly, adverse effects caused by other pneumotoxins - based on indications that TRPV3 appears to play fundamental roles in maintaining lung cell/tissue homeostasis during stress/after injury. This study is motivated by results showing that TRPV3 is expressed by human lung epithelial cells, TRPV3 is selectively activated by specific chemicals in PM obtained from burning multiple wood types, and this activation is coupled to acute pro-inflammatory and pro-apoptotic signaling. Additionally, TRPV3 is dynamically regulated and is involved in adaptive reprogramming of lung cells, sub-acute morphological changes in the airways of mice, and compromised lung function. Our hypothesis is that TRPV3 plays dual roles in mediating both the acute pro-inflammatory/cytotoxic effects of WBSPM as well as adaptation of lung cells to resist further damage to toxins and airway remodeling. The specific aims are to: 1) further delineate the role of TRPV3 in acute and chronic WBSPM pneumotoxicity; 2) decipher TRPV3, ER stress, COX2/PTGS2, and EGFR integration in lung injury and repair; and 3) evaluate TRPV3 as a universal mediator of WBSPM toxicity.