Role of Chromogranin A and its derived peptides in the context of gut physiology

胃肠道的功能在一定程度上是由胃肠道系统内不同类型的细胞产生和释放的一系列多肽激素所协调的。尽管关于多肽在肠道生物学中的作用积累了丰富的知识，但几乎可以肯定的是，肠道中还存在其他具有显著生理活性的多肽。肠道的主要功能是吸收和推进饮食中的营养物质，但它也形成了一种物理和免疫屏障。在过去的十年里，一种最初在肾上腺发现的新型蛋白质彻底改变了我们对免疫系统神经内分泌调节的看法。这种新的颗粒蛋白被称为嗜铬粒蛋白(CG)A，它定义了神经内分泌和生理机制如何调节的新范式。Granin蛋白家族储存在肠道水平的一些神经元的嗜铬颗粒中，以及存在于肠壁的特定类型的内分泌、免疫和神经内分泌细胞中。细胞和组织特异性的CGA已在胃肠道中被描述，产生小肽。然而，目前还不完全清楚哪些特定的小肽存在于肠道水平，以及它们如何影响胃肠道的生理功能，特别是平滑肌收缩和通透性。在这项研究计划中，我们建议扩展我们的知识，以阐明这些多肽的存在和生理作用，重点是它们对肠道平滑肌收缩和跨上皮通透性的潜在调节。我们相信，这些创新和新颖的研究将使我们能够扩大我们对CGA衍生多肽介导的通透性和平滑肌功能所涉及的细胞和分子机制的了解，解释作为细胞功能关键调节因素的作用，并有助于了解神经内分泌肽在肠道生理中的作用。这将对肠道生理学产生重大影响，因为它将为其他团队开辟新的途径，以更深入地描述CGA细胞和细胞内通路之间的相互作用。

Functions of the gastrointestinal (GI) tract are in part orchestrated by a host of peptide hormones produced and released from various cell types within the GI system. Despite the wealth of knowledge accumulated on the role of peptides in gut biology, it is almost certain that there are additional peptides with significant physiological activities in gut. The primary function of the intestine is the absorption and propulsion of dietary nutrients, but it also forms a physical and immunological barrier. During the last decade, a new type of protein, discovered initially at the adrenal gland, has revolutionized our thinking of the neuroendocrine regulation of the immune system. This new granin protein called Chromogranin (Cg) A has defined a new paradigm on how neuroendocrine and physiological mechanisms are regulated. The granin family of proteins is stored in chromaffin granules of some neurons present in the gut level, as well as specific types of endocrine, immune and neuroendocrine cells present at the gut wall. Cell and tissue specific CgA has been described in the GI tract, generating small peptides. However, it is not fully understood which specific small peptides are present at the gut level and how they affect gastrointestinal physiological functions, in particular smooth muscle contraction and permeability. In this research program, we propose to extend our knowledge to elucidate the presence and the physiological actions of these peptides, with a focus on their potential regulation of gut smooth muscle contraction and trans-epithelial permeability. We believe that these innovative and novel studies will allow us to expand our knowledge of the cellular and molecular mechanism involved in CgA-derived peptides mediated permeability and smooth muscle functions, explain roles as a key regulators of cellular function and help understand the role of neuroendocrine peptides on gut physiology. This will have a great impact in gut physiology as it will open new avenues for other teams to describe in a deeper approach the interaction between CgA cells and intracellular pathways.**