Funded Projects

Considerable attention has been focused on the identification of duplicate genes that have emerged since the human–chimpanzee divergence because of their potential to contribute to human-specific traits. CHRFAM7A, a human specific fusion gene between CHRNA7 and FAM7A/ULK1, is a putative negative regulator of the 7 nAChR. 7 nAChR ionotropic and metabotropic effects are linked to Ca2+ conductance, with 7 nAChR representing the highest level of Ca2+ conductance among the ACh receptors. There is an inverse relationship between channel open state and metabotropic activation, with the metabotropic effect taking place during receptor inactivation. 7 nAChR metabotropic receptor is the mediator of the cholinergic anti-inflammatory response through mononuclear cells of the innate immune system. Our preliminary data from human iPSC model indicates that human innate immune response is dependent on the CHRFAM7A genotype, including the TLR7 and TLR8 response implicated in Covid-19 infection. Aim 1: To decipher the effect of CHRFAM7A genotypes on 7 nAChR ionotropic and metabotropic function Electrophysiology and in vivo Ca imaging are correlated with CHRFAM7A genotypes. Aim 2: To identify genotype and PAMP interaction specific cytokine/chemokine signatures TLR agonists representing common PAMPs are used in a TaqMan based screen. Aim 3: Population based ex vivo and in vivo correlation for model validation: Double blind genotype-phenotype correlation study design: Human subject volunteers whom receive Covid-19 vaccination as standard of care are recruited for the clinical study. Monocytes are isolated prior to vaccination for ex vivo experiments. Ex vivo human macrophages are exposed to TLR stimulants to detect genotype specific activation dynamics for dsRNA, ssRNA, gram positive bacteria and gram negative bacteria. For the in vivo correlation, RNA and biomarker samples are collected before and after vaccination to characterize in vivo response. The IRB approved the study.