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Dietary Regulation of Pancreatic Digestive Enzymes

胰腺消化酶的饮食调节

基本信息

批准号：
7848676
负责人：
JOHN A WILLIAMS
金额：
$ 3.82万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848676
关键词：
Acinar Cell Acinus organ component Acute Address Adenovirus Vector Adherent Culture Adult Attention Caerulein Calcineurin Calcium Cell Cycle Cell Cycle Regulation Cell Lineage Cell division Cells Cholecystokinin Chronic Collagen Cyclin D1 Diet ERG gene Ensure Enzymes Ethionine Exocrine pancreas Extracellular Signal Regulated Kinases FOS gene Family member Feedback Gene Expression Gene Proteins Gene Targeting Genes Growth Growth Factor Hormonal Hormones Human In Vitro Individual Injury JUN gene Knowledge Lead MAPK8 gene MEKs Malignant neoplasm of pancreas Mediating Mitogen-Activated Protein Kinases Modeling Mus Natural regeneration Pancreas Pancreatic Diseases Pancreatitis Pathway interactions Pattern Plasma Protease Inhibitor Proteins Regulation Regulatory Pathway Role Signal Pathway Small Interfering RNA Stimulation of Cell Proliferation Techniques Tissues Transcription Factor AP-1 Transgenic Mice Work camostate chronic pancreatitis design extracellular feeding human FRAP1 protein in vitro Model in vivo inhibitor/antagonist inorganic phosphate loss of function protein expression public health relevance response

项目摘要

DESCRIPTION (provided by applicant): The overall aim of this work is to understand how the growth of the adult pancreas is regulated to provide an adequate supply of digestive enzymes. We hypothesize that growth can occur by two mechanisms. The first occurs in response to diet and hormones and involves stimulation of differentiated acinar cells to enter the cell cycle and divide. The second form of growth that occurs following tissue injury such as pancreatitis involves dedifferentiation, cell division and dedifferentiation and will be referred to as regeneration. Our primary model for hormonal stimulation of growth involves feeding the synthetic protease inhibitor, camostat to mice to increase plasma CCK. We have shown this growth requires the calcium activated phosphates calcineurin and the mTOR pathway, and is accompanied by the activation of the MAP kinases, ERK and JNK, and the expression of a number of early response genes including multiple c-Jun and c-Fos family members. In Specific Aim 1 we will study the mechanisms mediating mitogenesis and growth of differentiated cells driven by chronic CCK elevation. a) We will identify the cell cycle regulators activated by CCK. b) We will study target genes regulated by NFATs (regulated by calcineurin) and AP-1 (activated by MAP kinases) with particular attention to regulation of cell-cycle regulating genes such as cyclin D1 and PCNA and to endogenous feedback inhibitors such as MClP1 for calcineurin. In Specific Aim 2 we will determine the mechanisms mediating regeneration after tissue injury. We will study regeneration following two models of pancreatitis induced by ethionine and caerulein over-stimulation. a) We will determine how the pattern of gene expression is altered in regeneration in the presence and absence of CCK using CCK deficient mice. b) We will determine the importance of calcineurin and mTOR for regeneration using both pharmacological inhibitors and gene targeted mice. In Specific Aim 3 we will determine the regulatory mechanisms for CCK and Growth Factor stimulated growth of acinar cells in primary monolayer culture which serves as a model for growth similar to regeneration and in which proteins and siRNA can be expressed with adenoviral vectors. We will first characterize the dedifferentiation and establish the acinar cell origin of dividing cells by lineage tracing. We will then evaluate the importance of different signaling pathways and cell cycle components with a focus on the key role of c-jun and AP1. Overall, the project will lead to better understanding of pancreatic growth and assist in designing approaches to regulating pancreatic growth in humans. PUBLIC HEALTH RELEVANCE: A number of pancreatic diseases including acute and chronic pancreatitis and pancreatic cancer lead to a loss of functioning pancreatic tissue. Knowledge from this project should allow designing approaches to assist the human pancreas to regenerate and ensure an adequate supply of pancreatic digestive enzymes.

描述（由申请人提供）：这项工作的总体目标是了解成人胰腺的生长如何被调节以提供足够的消化酶供应。我们假设生长可以通过两种机制发生。第一种发生在对饮食和激素的反应中，涉及刺激分化的腺泡细胞进入细胞周期并分裂。胰腺炎等组织损伤后发生的第二种生长形式包括去分化、细胞分裂和去分化，被称为再生。我们的激素刺激生长的主要模型是给小鼠喂食合成蛋白酶抑制剂卡莫司他来增加血浆CCK。我们已经证明，这种生长需要钙活化磷酸钙调磷酸酶和mTOR途径，并伴随着MAP激酶、ERK和JNK的激活，以及包括多个c-Jun和c-Fos家族成员在内的许多早期反应基因的表达。在Specific Aim 1中，我们将研究慢性CCK升高驱动的有丝分裂和分化细胞生长的机制。a)我们将识别由CCK激活的细胞周期调节因子。b)我们将研究nfat（由calcalineurin调节）和AP-1（由MAP激酶激活）调控的靶基因，特别关注细胞周期调节基因如cyclin D1和PCNA的调控，以及内源性反馈抑制剂如calcalineurin的MClP1。在特异性目标2中，我们将确定组织损伤后介导再生的机制。我们将研究蛋氨酸和小蛋白过度刺激诱导的两种胰腺炎模型的再生。a)我们将使用CCK缺陷小鼠，确定在CCK存在和不存在的情况下，再生过程中基因表达模式是如何改变的。b)我们将使用药物抑制剂和基因靶向小鼠来确定钙调磷酸酶和mTOR对再生的重要性。在特异性目标3中，我们将确定CCK和生长因子在原代单层培养中刺激腺泡细胞生长的调控机制，这是一种类似再生的生长模型，其中蛋白质和siRNA可以用腺病毒载体表达。我们将首先描述去分化的特征，并通过谱系追踪确定分裂细胞的腺泡细胞起源。然后，我们将评估不同信号通路和细胞周期成分的重要性，重点关注c-jun和AP1的关键作用。总的来说，该项目将有助于更好地了解胰腺生长，并帮助设计调节人类胰腺生长的方法。公共卫生相关性：许多胰腺疾病，包括急性和慢性胰腺炎和胰腺癌，导致功能胰腺组织的丧失。从这个项目中获得的知识应该允许设计方法来帮助人类胰腺再生，并确保胰腺消化酶的充足供应。