Impact of chromogranin-A on gut smooth muscle contraction

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The capacity to adapt to environmental stresses is critical for the viability of all life forms, and this is valid also at the cellular level. The molecular players and pathways by which cells respond to stress are often evolutionarily conserved in higher organisms. The long-term goal of my Discovery research program is to identify the mechanisms underlying the gut physiological effects of some evolutionarily highly-conserved stress proteins known as the chromogranin (CHG)-A and its derived peptides. Due to the strategic location of enterochromaffin (EC) cells at the interface of the gut mucosa, CHGA and its derived peptides, found in EC cells, should play an important role in relation to gut physiology. But their roles remain to be described. Primary gut function is the digestion and the propulsion of dietary nutrients via the microbiota and smooth muscle contractions (SMCs). Microbiota imbalance and its fermentation by-products represented by short-fatty-acids (SCFAs) have been proven to contribute to chyme dysfunction propulsion and to the decrease in endocrine factors released from EC cells. As my group's previous work has shown effects of some of the CHGA derived peptides on colonic smooth muscle contraction, somatovisceral pain, permeability and gut microbiota, my short-term goals are conducted under the guiding hypothesis that in physiological conditions CHGA is a crucial component in maintaining the gut microbiota, fermenting by-products, SCFAs, and SMCs. My study aims to determine physiological targets of the CHGA pathway, forming the groundwork to delineate further the uncharacterized signal transduction pathways mediating these effects. AIM 1. To determine the effect of the absence of CHGA on the microbiota. Hypothesis: CHGA influences gut microbiota composition at the level of the feces and the mucosa. AIM 2. To determine the extent to which the microbiota composition impacts colonic SMC. Hypothesis: The modification of the gut microbiota and SCFAs in the absence of CHGA influence SMC. AIM 3. To define if a fecal microbiota transfer (FMT) can rescue the disturbance of the SMC in the absence of CHGA. Hypothesis: Restoration of a conventional microbiota normalizes SMC in CHGA-/- mice Through the CHGA-deficient mouse colony established at my university, I will decipher how the lack of CHGA influences SMC and the enteric nervous system (organ bath technique) and the gut microbiota (metagenomic technique, proteomics). Pharmacological studies will delineate the pathways implicated. The work will provide opportunities to HQP to work in a multidisciplinary environment and foster their development to independent scientists. Over this cycle, PhD student (Diarra), who has initiated the studies, will be assigned to the Aim1. Ph.D. & MSc students recruited in summer 2023 will complete Aim 3. MSc student recruited in Summer 2022 will work on Aim 2. BSc summer students will help graduate students.