Delineating physiological and toxic impact of TnP on aryl hydrocarbon receptor (AhR) signaling through morphometric and transcriptomic profiling using the zebrafish embryo model

• Grant number: 21/08411-6
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: December 13, 2021
• End date: August 12, 2022
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Monica Valdyrce dos Anjos Lopes Ferreira
• Grantee: Geonildo Rodrigo Disner
• Supervisor: Emma Elisabeth Wincent
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Institution abroad: Karolinska Institutet, Sweden
• Associated to the scholarship: 19/27677-7 - Study of the induction of regulatory microRNAs by TNP dependent on Aryl hydrocarbon Receptor (AhR) activation, BP.PD

Abstract

Our group identified in the venom of the fish Thalassophryne nattereri a novel cyclic peptide, TnP, in a preclinical development stage indicated for chronic inflammatory diseases such as asthma and multiple sclerosis. Recent data show its valuable potential as a safe anti-inflammatory drug due to its ability to control the traffic and activation of leukocytes in response to inflammation. In parallel, the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor historically known for its toxic responses to manufactured pollutants, has been pointed as a crucial molecule in several biological activities. AhR participates in multiple physiological processes in health and diseases, particularly in immune regulation, inflammatory response, tumorigenesis, and cellular differentiation, among many other pathological conditions. Originally, the AhR was discovered due to the ability of various chemicals and drugs to induce cytochrome P450 and hence alter the metabolism and pharmacokinetics of other drugs, which has implications for clinical practice. Since zebrafish (Danio rerio) can be used at multiple stages in drug discovery and offer several advantages, such as the isolated innate immune system, which is well-conserved between zebrafish and humans, it is extremely useful to assess dysregulation of the inflammatory response. We hypothesized that in an LPS-induced inflammation model using zebrafish, the TnP might influence AhR signaling pathways, which, in turn, control the transcription of inflammatory genes, regulatory non-coding RNA, and homeostasis. Thus, this study aims to elucidate molecular mechanisms resulting from the TnP and AhR cross-talk and evaluate the TnP activity during the inflammatory response both in the presence or absence of AhR. (AU)