Acetylcholine (ACh) is one of the most important neurotransmitters in the peripheral and central nervous systems. However, it is increasingly recognized that ACh is also a key molecule for signaling via nicotinic acetylcholine receptors (nAChRs) in non-neuronal cells. Mounting evidence indicates that subtypes of ?9-containing nAChRs are critical receptors of ACh in these non-neuronal cells. These receptors are implicated in a plethora of functions including immune function, cell migration and the stress response. Consequently, these nAChRs have been implicated in diseases ranging from chronic pain to cancer-cell proliferation. Unfortunately, study of these ?9-containing nAChRs is severely limited because of the lack of selective ligands. There are no ligands selective for human ?9-containing nAChRs. Furthermore, existing ligands are unable to discriminate among ?9-containing nAChR subtypes in any tested species. To address this problem, conotoxins that are antagonists of ?9-containing nAChRs will be exploited.
Aim 1 will develop selective antagonists for the human ?9 nAChR. This will be accomplished through iterative synthesis of analogs of ?-conotoxin RgIA and by development of newly discovered ?-conotoxins.
Aim 2 will characterize, for the first time, new families of conotoxins that target ?9-containing nAChRs. These will be developed to enable the selective block of subtypes of these nAChRs. A long-term goal is to use existing ligands, together with newly developed toxins to gain mechanistic insight into the hypothesized role of ?9-containing nAChRs in preventing chronic pain that ensues following nerve injury.
Aim 3 will use developed ligands to study the role of block of ?9-containing nAChRs in models of breast cancer.
This proposal will develop novel molecules for the study of cell surface proteins known as alpha9 nicotinic receptors. These receptors regulate diverse functions including immune system function and cell growth. The ability to pharmacologically manipulate these receptors has the therapeutic potential to treat chronic pain and breast cancer.
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