Our research is centered on acetylcholine functioning; with a focus on molecular biology and genomic applications to the study of cholinergic signaling, and especially on its microRNA regulation. Our work spans both basic and biomedical studies on cholinergic signaling in health and disease, particularly on anxiety-related topics.
MicroRNAs (miRNAs) rapidly emerge as global regulators of gene expression, yet the full scope of their roles in brain functioning is largely unknown. We combine advanced sequencing technologies with computational and transgenic engineering tools to investigate miRNA functions in the healthy and diseased brain, in particular acetylcholine-related processes. Our studies discovered cholinergic brain-to-body regulation of anxiety and inflammation and found "CholinomiRs", miRNA controllers of multiple cholinergic genes, several of them cloned and characterized in-house, that compete with each other on suppressing their targets. We test CholinomiR-based interventions with a focus on diseases involving impaired ACh signaling, anxiety, inflammation and neurodegeneration. In human volunteers, we find cholinergic-associated pulse increases under fear of terror; and elevated trait anxiety, blood pressure and inflammation under inherited interference with acetylcholinesterase (AChE)-targeting CholinomiRs. In stressed mice and engineered mice, we study cholinergic changes associated with CholinomiR increases under stress, inflammation and neurodegeneration, whereas in Alzheimer’s brains we see massive CholinomiRs decline, accompanying modifications in alternative splicing and transcript processing that differs from that of Parkinson’s disease and which may be reversed by antisense oligonucleotide treatment.