Protective Signaling Pathway in Alcohol-Induced Pancreatitis

酒精性胰腺炎的保护性信号通路

基本信息

批准号：
9917676
负责人：
TIEN C KO
金额：
$ 18.43万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917676
关键词：
Activins Alcoholic Pancreatitis Alcohols BMPR2 gene Bone Morphogenetic Proteins Cells Complex Development Diabetes Mellitus Disease Disease Outcome Disease Progression Effector Cell Equilibrium Functional disorder Future Human In Vitro Inflammatory Knock-out Knockout Mice Knowledge Link Lipopolysaccharides Malignant neoplasm of pancreas Mediating Modeling Mus Pancreas Pancreatic Diseases Pancreatitis Patients Play Principal Investigator Regulation Risk Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Testing Therapeutic Therapeutic Intervention Time Tissue Sample Transforming Growth Factors acute pancreatitis alcoholic chronic pancreatitis bone morphogenetic protein receptors chronic alcohol ingestion chronic pancreatitis clinically relevant cohesion effective therapy experimental study in vivo innovation insight member mouse model novel prevent programs public health relevance response stellate cell stressor therapeutic development

Activins Alcoholic Pancreatitis Alcohols BMPR2 gene Bone Morphogenetic Proteins Cells Complex Development Diabetes Mellitus Disease Disease Outcome Disease Progression Effector Cell Equilibrium Functional disorder Future Human In Vitro Inflammatory Knock-out Knockout Mice Knowledge Link Lipopolysaccharides Malignant neoplasm of pancreas Mediating Modeling Mus Pancreas Pancreatic Diseases Pancreatitis Patients Play Principal Investigator Regulation Risk Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Testing Therapeutic Therapeutic Intervention Time Tissue Sample Transforming Growth Factors acute pancreatitis alcoholic chronic pancreatitis bone morphogenetic protein receptors chronic alcohol ingestion chronic pancreatitis clinically relevant cohesion effective therapy experimental study in vivo innovation insight member mouse model novel prevent programs public health relevance response stellate cell stressor therapeutic development

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项目摘要

Principal Investigator/Program Director (Last, first, middle): KO, Tien C., MD PROJECT SUMMARY Chronic alcohol consumption is the most common cause of chronic pancreatitis (CP), a devastating fibro-inflammatory disease of the pancreas with no effective therapy. The unmet need for CP therapy is largely due to fundamental gaps in our understanding of the complex mechanisms that regulate CP progression. Transforming growth factor (TGF)-β and bone morphogenetic protein (BMP), members of the TGF-β superfamily, play pro- and anti-fibrogenic roles, respectively, in CP. Gremlin1 (Grem1), a prominent endogenous BMP antagonist, is elevated in CP. Grem1 can be experimentally induced by TGF-β, alcohol metabolite and cerulein in vitro in pancreatic stellate cells (PSCs), the key effector cells in CP. Grem1 can block BMP signaling in these cells. Thus, a balance between BMP and TGF-β signaling through Grem1 regulation may dictate CP progression. The objective of this proposal is to understand the protective role of BMP signaling during the disease progression. This study will take both in vivo approach by employing two alcohol (A)-induced CP mouse models in conditional BMP receptor and Grem1 knockout mice, and in vitro approach by using PSCs for mechanistic studies. Human pancreatic cells and tissue samples will be utilized for validating key findings from mouse studies. Two Specific Aims will be pursued. Specific Aim 1 determines the anti-fibrogenic effects of BMP signaling in alcohol-induced chronic pancreatitis by evaluating whether blocking BMP signaling exacerbates CP and how BMP signaling opposes TGF-β signaling. Specific Aim 2 investigates the mechanisms of suppression of BMP signaling in alcohol-induced chronic pancreatitis by examining whether Grem1 knockout ameliorates CP, how alcohol enhances Grem1 expression, and whether Grem1 levels correlate with TGF-β and BMP signaling in human CP. The proposed study is expected to provide mechanistic insights into a novel protective key signaling pathway in CP, which will lead to a better understanding of the disease progression and innovative approaches to CP therapy. 1

首席研究员/计划主管（最后，第一，中间）：KO，Tien C.，医学博士项目摘要慢性饮酒是慢性胰腺炎（CP）的最常见原因，这是一种毁灭性的没有有效治疗的胰腺纤维炎症疾病。对CP治疗的需求是在很大程度上是由于我们对调节CP的复杂机制的理解中的基本差距进展。转化生长因子（TGF）-β和骨形态发生蛋白（BMP）， TGF-β超家族，分别在CP中扮演促纤维化和抗纤维化作用。 Gremlin1（Grem1），一个突出的内源性BMP拮抗剂在CP中升高。 GREM1可以通过TGF-β，酒精实验诱导胰腺星状细胞（PSC）中的代谢产物和谷蛋白，CP中的关键效应细胞。 Grem1可以阻止这些细胞中的BMP信号传导。这是BMP和TGF-β信号通过GREM1之间的平衡调节可能决定CP的进展。该提议的目的是了解受保护的角色疾病进展过程中BMP信号的传导。这项研究将通过使用有条件的BMP受体和GREM1敲除小鼠中的两个酒精（A）诱导的CP小鼠模型，以及通过使用PSC进行机械研究的体外方法。人类胰腺细胞和组织样品将是用于验证小鼠研究的关键发现。将追求两个具体的目标。具体目标1 通过评估阻止BMP信号是否加剧CP以及BMP信号传导如何反对TGF-β 信号。具体目标2研究了酒精诱导的BMP信号抑制的机制慢性胰腺炎通过检查GREM1敲除是否可以改善CP，酒精如何增强GREM1 表达以及GREM1水平是否与人CP中的TGF-β和BMP信号相关。这拟议的研究有望为新型受保护的钥匙信号通路提供机械见解在CP中，这将使人们更好地了解疾病进展和创新方法 CP疗法。 1