Alcohol, Retinoids and Pancreas Biology

摘要 我们建议研究慢性饮酒是如何诱发胰腺炎和糖尿病的， 类维生素A（维生素A及其天然代谢物）可能在这一过程中。小鼠将被喂食酒精- 含有或等热量控制Lieber-DeCarli饮食。将通过使用以下物质在这些小鼠中诱导胰腺炎： 高剂量的雨蛙肽，如文献中所述。胰腺的健康和功能，包括内分泌和 将评估外分泌，沿着胰腺类维生素A水平和作用的可能破坏。我们的研究 将采用野生型小鼠和缺乏胰腺类维生素A储存、卵磷脂： 视黄醇酰基转移酶缺陷（Lrat-/-）小鼠。将被检验的总体假设是， 消耗损害胰腺类维生素A代谢和行动，无论是在胰腺外分泌和 胰岛，这些损害有助于酒精对胰腺疾病的影响， 功能障碍我们提出两个具体目标。 在具体目标1中，我们将研究长期饮酒对胰腺的影响，重点是 酒精依赖性实验性慢性胰腺炎与其影响的关系 并受胰腺类维生素A储存的影响。在这里，我们将确定慢性酒精喂养如何影响 在具有正常胰腺类维生素A储存的小鼠和不具有胰腺类维生素A储存的小鼠中， 类维生素A储存在他们的胰腺星状细胞（PSC）中。由于PSC类维生素A储存的损失与 胰腺纤维化和胰腺炎的发展，我们希望直接建立胰腺纤维化的作用， 类维生素A储存在减缓或阻止酒精引起的胰腺疾病的发展。 在具体目标2中，我们将探讨长期饮酒对胰腺内分泌的影响， 特别关注酒精引起的胰岛功能变化的影响，以及这是如何发生的。 与全反式维甲酸（ATRA）信号相关。ATRA是维持正常血糖所必需的 刺激胰岛β细胞分泌胰岛素。我们的初步数据表明ATRA的作用 胰岛α细胞分泌胰高血糖素的信号传导。在这里，我们建议调查 酒精如何导致正常胰腺内分泌功能的丧失，以及这是否涉及破坏 正常的ATRA信号 总的来说，我们提出的研究将扩大对酒精对人体的毒性作用的理解。 胰腺

ABSTRACT We are proposing to investigate how chronic alcohol consumption induces pancreatitis and diabetes and the role that retinoids (vitamin A and its natural metabolites) may have in this process. Mice will be fed either the alcohol- containing or the isocaloric control Lieber-DeCarli diet. Pancreatitis will be induced in these mice by the use of high doses of caerulein as described in the literature. Pancreatic health and functions, both endocrine and exocrine, along with possible disruptions of pancreatic retinoid levels and actions, will be assessed. Our studies will employ wild type mice and an induced mutant mouse model that lacks pancreatic retinoid stores, lecithin: retinol acyltransferase-deficient (Lrat-/-) mice. The overall hypothesis that will be tested is that chronic alcohol consumption impairs pancreatic retinoid metabolism and actions, both in the exocrine pancreas and in pancreatic islets, and that these impairments contribute to alcohol's effect on pancreatic disease and dysfunction. We propose 2 Specific Aims. In Specific Aim 1, we will investigate the effects of chronic alcohol consumption on the pancreas, focusing on the relationship between alcohol-dependent experimentally induced chronic pancreatitis and how this influences and is influenced by pancreatic retinoid stores. Here we will identify how chronic alcohol-feeding affects the development of pancreatitis in mice that possess normal pancreatic retinoid stores and in mice that possess no retinoid stores in their pancreatic stellate cells (PSCs). Since the loss of PSC retinoid stores is associated with the development of pancreatic fibrosis and pancreatitis, we expect to establish directly a role for pancreatic retinoid stores in slowing or blocking the development of alcohol-induced pancreatic disease. In Specific Aim 2, we will explore the effects of chronic alcohol consumption on the endocrine pancreas, focusing specifically on the effect of alcohol-induced changes in pancreatic islet functions and how this is associated with all-trans-retinoic acid (ATRA) signaling. ATRA is required for maintaining normal glucose stimulated insulin secretion from the beta-cells of pancreatic islets. Our preliminary data suggest a role for ATRA signaling in glucagon secretion from the alpha-cells of pancreatic islets. Here, we are proposing to investigate how alcohol-induces the loss of normal pancreatic endocrine functions and whether this involves disruption of normal ATRA signaling. Collectively, the research we are proposing will extend understanding of the toxic effects of alcohol on the pancreas.