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Mitigating pro-inflammatory non-agonist molecules from tobacco smoke

Institution: University of California, Los Angeles
Investigator(s): Gerard Wong,
Award Cycle: 2019 (Cycle 29) Grant #: T29IP0544 Award: $482,840
Subject Area: Environmental Exposure/Toxicology
Award Type: High Impact Pilot Award

Initial Award Abstract
We investigate how cigarette smoke and e-cigarette associated chemical compounds can influence our immune system, which can influence disease and health outcomes on tobacco related cancer, respiratory diseases, and cardiovascular diseases. We have recently discovered a new form of molecular recognition which in principle allows the innate immune system to detect and respond to cigarette smoke associated compounds without having receptors specific to them. Having specific receptors that bind to specific ligand molecules has been one of the central paradigms of molecular biology, and usually described as a 'lock and key' mechanism. From our preliminary data on autoimmune diseases, we find something drastically different. New molecules that do not normally bind to these receptors can bind to the ligand molecules (the 'key' molecules that open the 'lock'), and form well-ordered crystals with them. This composite molecular complex not only binds the receptors ('opens the lock'), it causes a massive amplification of the immune system (by ~20000%). This effect occurs for psoriasis, lupus, and rheumatoid arthritis, which are precisely the autoimmune diseases to which smokers have increased susceptibility. In our preliminary analysis, we identify chemicals associated with cigarette smoke that are expected to have this ability to influence the immune system, which can broadly impact many smoking related health conditions. In our proposal, we propose novel ways to turn off this form of pathological immune amplification by custom-designed molecules that outcompete the cigarette smoke associate compounds and prevent them from forming these composite molecular complexes, which is a crucial step in the activation mechanism.