Nociception is the sensory nervous system that detects harmful stimuli including excessive heat, cold, toxic chemicals, and noxious mechanical stimulations. Transient receptor potential (TRP) channels are a group of evolutionarily conserved ion channels consisting of 4 subunits, each with 6 transmembrane spans, and detect a variety of external and internal nociceptive stimuli. Due to their critical roles in nociception, it is essential to understand the mechanisms that regulate TRP channels and subsequent nociception. Here, I investigated two distinct types of regulation of Drosophila transient receptor potential cation channel A1 (TrpA1): regulation via the expression of different TrpA1 isoforms, and via its binding with associated proteins. I found that one of the TrpA1 isoforms, TrpA1(E), inhibits the thermal responses of other TrpA1 isoforms in vitro. I also identified potential TrpA1 binding partners through Co- immunoprecipitation (Co-IP) and mass spectrometry analysis. These binding partners need further validation and characterization through biochemical, cellular, and behavioral assays to illustrate their roles in nociception, and may serve as potential drug targets for chronic pain.

Among many putative genetic risk variations reported to date, the ApoE4 allele remains the most common genetic risk factor for late-onset AD, and is associated with both an increase in incidence and a decrease in age of clinical onset. The majority of ApoE is produced in the: 1) central nervous system (CNS) by astrocytes to transport lipids between cells and modulate the inflammatory response; and 2) liver, where it facilitates lipid uptake into peripheral tissues via low-density lipoprotein (LDL) receptors. Consistent with its dual roles, genetic knockout of ApoE increases the risk for atherosclerosis, but it also dramatically improves AD phenotypes in mouse models. Antisense oligonucleotide (ASO) based modulation of CNS ApoE has only marginal effects on AD phenotypes, suggesting that post-embryonic silencing of ApoE is not a viable therapeutic strategy. However, the recent development of novel CNS siRNA chemical structures enables widespread distribution and potent target silencing throughout the brain. Using this technology, we demonstrate that liver and brain ApoE pools are spatially and functionally distinct, and that complete silencing of brain, not liver, ApoE results in robust reduction of amyloid plaque formation, without impacting systemic cholesterol. Furthermore, RNAseq analysis shows minimal off target effects of the siRNAs and identifies immune modulation and metabolic alterations as potential mechanisms behind ApoE’s role in plaque formation and clearance. Moving forward, these results build upon the rationale to modulate ApoE expression and provide the technology necessary to further evaluate the impact ApoE silencing in AD and other neurodegenerative diseases

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