Impact of chromogranin-A on gut smooth muscle contraction

适应环境压力的能力对于所有生命形式的生存能力至关重要，这在细胞水平上也是有效的。细胞对压力做出反应的分子和途径在高等生物中通常是进化保守的。我的发现研究计划的长期目标是确定一些进化上高度保守的应激蛋白（称为chromogranin（CHG）-A及其衍生肽）的肠道生理作用的机制。由于肠嗜铬（EC）细胞在肠道粘膜界面的战略位置，CHGA及其衍生的肽，发现在EC细胞，应该发挥重要作用，在肠道生理。但它们的作用仍有待描述。主要的肠道功能是通过微生物群和平滑肌收缩（SMC）消化和推进膳食营养素。微生物群失衡及其以短脂肪酸（SCFAs）为代表的发酵副产物已被证明有助于食糜功能障碍推进和EC细胞释放的内分泌因子的减少。由于我的小组以前的工作已经显示了一些CHGA衍生肽对结肠平滑肌收缩，躯体内脏疼痛，渗透性和肠道微生物群的影响，我的短期目标是在指导假设下进行的，即在生理条件下CHGA是维持肠道微生物群，发酵副产物，SCFA和SMC的关键组成部分。我的研究旨在确定CHGA通路的生理靶点，为进一步描述介导这些效应的非特征性信号转导通路奠定基础。AIM 1.确定不存在CHGA对微生物群的影响。假设：CHGA影响粪便和粘膜水平的肠道微生物群组成。 AIM 2.确定微生物群组成影响结肠SMC的程度。假设：在不存在CHGA的情况下，肠道微生物群和SCFA的改变影响SMC。AIM 3.确定粪便微生物群转移（FMT）是否可以在不存在CHGA的情况下挽救SMC的紊乱。假设：通过在我的大学建立的CHGA缺陷小鼠群体，我将破译缺乏CHGA如何影响SMC和肠神经系统（器官浴技术）和肠道微生物群（宏基因组技术，蛋白质组学）。药理学研究将描述所涉及的途径。这项工作将为HQP提供在多学科环境中工作的机会，并促进他们向独立科学家的发展。在这个周期中，博士生（迪亚拉），谁已经启动了研究，将被分配到目标1。博士2023年夏季招收的硕士学生将完成目标3。2022年夏季招收的理学硕士学生将致力于Aim 2。BSC暑期学生将帮助研究生。

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.