A Clinical Center to Study Immunological and Hormonal Biomarkers for the Diagnosis, Prediction and Treatment of Chronic Pancreatitis and its associated development to Diabetes and Pancreas Cancer

 申请加入慢性胰腺炎、糖尿病和胰腺癌研究联盟(CSCPDPC)，旨在研究免疫系统和激素因素在慢性胰腺炎中的作用及其与糖尿病和胰腺癌发展的关系。我们的临床前免疫学研究表明，巨噬细胞、细胞因子和星状细胞在预测纤维化的发展中起着关键作用。我们的临床前激素研究重点是神经梅毒素U(NMU)，这是一种对胰岛素分泌具有抑制作用的神经肽。它还因其对巨噬细胞和细胞因子的潜在作用以及在伤害感受中的作用而引起人们的兴趣。这些观察结果可能进一步深入了解慢性胰腺炎的自然病史，以及在胰腺癌的背景下理解糖尿病发展的机制。为了应对这种RFA，我们组建了一支强大的科学团队，在临床胰腺炎、免疫学和发育生物学方面拥有广泛的互补专业知识。我们的建议在几个具体方面高度响应了RFA。(1)作为一个临床中心，我们有经验和能力开发和执行标准化的多中心方案，以纳入慢性胰腺炎、糖尿病和胰腺癌患者队列。在这项建议中，我们专门为慢性胰腺炎患者的前瞻性纵向队列制定了一项方案，同时伴随着血液、尿液、粪便和胰液分泌素刺激的注释性生物信息库。我们也有两个可用的血液储存库；一个用于胰腺炎患者，另一个用于胰腺癌患者，可与该联盟共享，以支持回顾性研究。(2)我们将开发和验证细胞因子图谱，以帮助诊断慢性胰腺炎并预测相关并发症的可能性。这些也可能导致支持阻止纤维化的临床试验的目标。(3)我们将发展和 验证基于血清的NMU分析可能有助于诊断3c型糖尿病和胰腺癌诱发的糖尿病。这可能会导致新的诊断测试，以检测早期胰腺癌。与其他中心合作进一步调查和验证这些新观察结果的机会仍然是一个令人兴奋的机会，可以加快研究，改变慢性胰腺炎治疗及其相关并发症，如胰源性糖尿病和胰腺癌的发展。

 DESCRIPTION (provided by applicant): This application to join the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreas Cancer (CSCPDPC), seeks to examine the role of the immune system and of hormonal factors in chronic pancreatitis and its relationship to the development of diabetes and pancreas cancer. Our pre-clinical immunological studies suggest a pivotal role for macrophages, cytokines and stellate cells in predicting the development of fibrosis. Our pre-clinical hormonal studies focus on neuromedin U (NMU), which is a neuropeptide with an inhibitory effect on insulin secretion. It is also of interest for its potentil effect on macrophages and cytokines and its role in nociception. These observations may provide further insight into the natural history of chronic pancreatitis, and mechanisms for understanding the development of diabetes in the context of pancreas cancer. In response to this RFA, we have formed a strong scientific team with broad complementary expertise in clinical pancreatitis, immunology, and developmental biology. Our proposal is highly responsive to the RFA in several specific ways. (1) As a Clinical Center, we have the experience and capacity to develop and execute standardized multi-center protocols for enrolling cohorts of patients with chronic pancreatitis, diabetes and pancreas cancer. In this proposal, we specifically delineate a protocol for a prospective longitudinal cohort of patients with chronic pancreatitis accompanied with an annotated bio-repository of blood, urine, stool, and secretin stimulated pancreas fluid. We also have available 2 repositories of blood; one for patients with pancreatitis and the other of pancreas cancer, that are available for sharing with the consortium to support retrospective studies. (2) We will develop and validate cytokine profiles that may facilitate diagnosis of chronic pancreatitis and predict likelihood of associated complications. These may also lead to targets to support clinical trials to halt fibrosis. (3) We will develop and validate a serum-based assay of NMU that may help diagnose type 3c diabetes mellitus and pancreatic cancer-induced diabetes. This may lead to novel diagnostic tests to detect pancreatic cancer at earlier stages. The opportunity to further investigate and validate these novel observations in collaboration with other centers remains an exciting opportunity to accelerate research that could change chronic pancreatitis management and its associated complications of pancreatogenic diabetes and pancreas cancer development.