Biomarkers to assess progression of alcohol induced chronic pancreatitis.

描述（由申请人提供）：拟议申请的第一个目标是通过完成公共卫生硕士课程，让我有受保护的时间进行临床生物统计学，生物标志物开发，研究设计和流行病学方面的高级培训。经过严格的培训计划在此应用程序中概述，我将在一个很好的位置过渡到一个独立的临床研究生涯。所提出的研究的第二个目的是基于胰腺分泌物组中炎性和纤维化细胞因子的表达，开发酒精诱导的CP中疾病进展的预测模型。待检验的中心假设是“胰腺中炎症和纤维化途径的激活，如胰腺分泌物中的细胞因子谱所反映，可预测CP的疾病进展，并可通过饮酒、临床和行为因素进行调节”。该假设将通过两个相互关联的特定目的进行检验：（1）开发一种使用胰液促炎细胞因子水平作为生物标志物的模型，以预测CP受试者中器官衰竭的发展和疾病阶段的进展，以及（2）特定行为因素，包括饮食和饮酒模式分别与胰液细胞因子谱。我们期望表明，细胞因子的表达模式预测外分泌衰竭，内分泌衰竭，假性囊肿和/或胆管狭窄的发展。我们还希望证实，结局数量越多，CP受试者的死亡风险越大。这些研究的基本原理是，它们将提供一种在CP中以可量化但具有临床意义的方式获取结局的方法，而这种方法目前尚不可用。此外，它将允许开发基于胰腺分泌物组中的生物标志物的预测模型，其将允许量化发展上述一种或多种结果的可能性。它们还将为今后几年对该模式的前瞻性验证奠定基础。通过这些基于酒精相关CP受试者胰腺分泌组的生物标志物发现的创新研究，这些研究与国家酒精滥用和酒精中毒研究所（NIAAA）的优先事项直接一致。 公共卫生相关性：慢性胰腺炎（CP）是酒精中毒的一种常见和关键的终末器官效应;没有可靠的生物标志物来评估其严重程度和进展。该项目旨在开发有效的CP生物标志物，作为替代临床终点，以更好地进行临床管理和未来的治疗试验。该提案与国家酒精滥用和酒精中毒研究所的战略计划直接一致，以开发酒精相关终末器官损伤的生物标志物。

DESCRIPTION (provided by applicant): The first objective of the proposed application is to allow me the protected time for advanced training in clinical biostatistics, biomarker development, research study design, and epidemiology through completion of the Masters in Public Health program. After the rigorous training program outlined in this application, I will be in an excellent position to transition to an independent clinical research career. The second objective of the proposed studies is to develop a predictive model of disease progression in alcohol induced CP based on the expression of inflammatory and fibrogenic cytokines in the pancreatic secretome. The central hypothesis to be tested is that the 'Activation of inflammatory and fibrogenic pathways in the pancreas, as reflected in the cytokine profile in pancreatic secretions, predicts disease progression in CP and can be modulated by alcohol consumption, clinical and behavioral factors'. This hypothesis will be tested by two inter-related specific aims; (1) To develop a model using pancreatic juice pro-inflammatory cytokine levels as biomarkers to predict the development of organ failure and progression of disease stage in subjects with CP and, (2) specific behavioral factors including diet and patterns of alcohol consumption versus pancreatic juice cytokine profiles respectively. We expect to show that patterns of cytokine expression predict the development of exocrine failure, endocrine failure, pseudocyst and/or biliary stricture. We further expect to confirm that the more the number of outcomes, the greater the risk of mortality in subjects with CP. The rationale for these studies is that they will provide a way to capture outcomes in a quantifiable, yet clinically meaningful, way in CP which is not currently available. Moreover, it will allow development of a predictive model based on biomarkers in the pancreatic secretome that will allow quantification of the likelihood of developing one or more of the outcomes noted above. They will also set the stage for prospective validation of the model in subsequent years. By these innovative studies of biomarker discovery based on the pancreatic secretome in subjects with alcohol related CP, these studies are directly aligned with the priorities of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). PUBLIC HEALTH RELEVANCE: Chronic pancreatitis (CP) is a common and critical end-organ effect of alcoholism; there are no robust biomarkers to assess its severity and progression. This project aims at developing valid CP biomarkers to serve as surrogate clinical endpoints for better clinical management of and future therapeutic trials. This proposal is directly aligned with the strategic plan of National Institute of Alcohol Abuse and Alcoholism to develop biomarkers for alcohol related end organ damage.