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Role of immune cells in chronic pancreatitis

免疫细胞在慢性胰腺炎中的作用

基本信息

批准号：
9921368
负责人：
Aida Habtezion
金额：
$ 44.85万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-05 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9921368
关键词：
Acinar Cell Affect Animal Model Automobile Driving Behavior Cell Communication Cell physiology Cells Chronic Clinical Coculture Techniques Collagen Data Development Disease Disease Progression Endocrine Experimental Models Extracellular Matrix Degradation Extracellular Matrix Proteins Fibronectins Fibrosis Goals Host Defense Human Immune Immune response Immune system In Vitro Inflammation Islet Cell Lead Leukocytes Lipopolysaccharides Malignant neoplasm of pancreas Mediating Methods Operative Surgical Procedures Pancreas Pathogenicity Pathway interactions Patients Phenotype Play Process Research Risk Factors Role Source Specimen Stenosis System T-Lymphocyte Testing Therapeutic Therapeutic Agents Tissues Transgenic Animals acute pancreatitis burden of illness chronic abdominal pain chronic pancreatitis clinically significant cytokine driving force fibrogenesis in vivo injured innovation macrophage monocyte novel novel therapeutics operation pancreas development public health relevance stellate cell wound healing

项目摘要

DESCRIPTION (provided by applicant): Chronic pancreatitis (CP) is characterized by inflammation, fibrosis, and loss of pancreatic cells. CP can lead to sufficient tissue destruction and result in exocrine and endocrine insufficiency as well as difficult to treat chronic abdominal pain. The management of CP is challenging as there are no effective methods that can stop progression or reverse the disease. In addition, CP is a risk factor for the development of pancreatic cancer. Absence of progress in CP therapy in part is due to lack of understanding in mechanisms that potentially can either reverse or halt the disease. Recent in vitro and in vivo studies have shown objectively the role of activated pancreatic stellate cells (PSCs) in fibrogenesis in CP. PSCs play a central role in disease progression by regulating the synthesis and degradation of extracellular matrix proteins. Activation of PSCs is increased by cytokines from injured acinar cell and infiltrating leukocytes (e.g. macrophages). However, the mechanisms by which macrophages trigger and sustain the fibrotic processes are not fully understood. Our initial studies show that subset of macrophages (known as M2) are dominant in CP as compared to acute pancreatitis (AP), which is dominated by a different subtype of macrophages (M1). We hypothesize that unlike M1, M2 macrophages promote pancreatic fibrosis through sustained activation of PSCs, and in turn the activated PSCs enhance macrophage polarization towards M2 and propose mechanisms involved in macrophage-PSCs interaction to promote progression of CP. To achieve this goal in aim 1, we use animal models of acute and chronic pancreatitis in order to characterize immune responses associated with CP. Under aim 2, we will determine the role and source of macrophage subpopulation in CP. Specifically, we propose to test and study subtypes of macrophages and cytokines that are essential in the development of CP. Under aim 3, we will identify mechanisms via which macrophages affect PSC function and how PSCs in turn affect macrophage polarization and behavior using various co-culture systems and in vivo using transgenic animals that allow testing of pertinent pathways in the immune responses. When possible human PSCs (isolated from surgical specimens) and monocyte/macrophages will be used to confirm and identify pathways involved. Our proposed studies are novel because they focus on the immune responses associated with CP, macrophage plasticity, and have the potential to shift paradigm in the field by proposing mechanisms that can either halt or reverse CP, and thus alter the natural course of the disease. In addition to the gained understanding of immune mechanisms that mediate and/or allow progression of CP, the potential impact of this project is of great clinical significance, as our studies may lead to development of novel therapies that can change how we manage patients with CP.