Grant: Discovery Grants Program - Individual

Introduction: The human body tightly regulates local and systemic immune responses. It is becoming increasingly clear that the neurotransmitter acetylcholine plays a vital role in these processes, even though this molecule has been traditionally thought to only be involved in nervous functions. To work, acetylcholine must bind to one of 16 nicotinic acetylcholine receptors. One of these receptors, known as the 7 nicotinic acetylcholine receptor, is best known for its anti-inflammatory properties when targeted by nicotine. However, we have accumulating evidence that the 9 nicotinic acetylcholine receptor is a key player in immune regulation. In addition, recent studies have shown that T lymphocytes can shape immune responses via their own synthesis of acetylcholine, which was previously thought to only be produced by neurons. Our preliminary data show that other non-neuronal cells, such as those found in the bone marrow, are also able to produce ACh. The use of acetylcholine may therefore be more prevalent than originally thought. Objective and hypothesis: The main objective of this proposal is to explore how non-neuronal acetylcholine and nicotinic acetylcholine receptors control immune responses. We hypothesize that many immune cells themselves produce acetylcholine to communicate with neighboring immune cells. Acetylcholine then acts on 7 and 9 nicotinic acetylcholine receptors, also expressed by various immune cells. The interaction between acetylcholine and its receptors activates signals within immune cells and changes the way they function. Significance: This proposal will characterize the role of acetylcholine and its receptors in immune regulation. The discovery of the mechanisms involved would be highly novel to the field, and as such, we will gain a much better understanding of how the body maintains immunological stability.