Molecular Pathomechanism of Hereditary Pancreatitis

描述（由申请人提供）：本拨款提案的广泛、长期目标是了解与人类慢性遗传性胰腺炎相关的遗传危险因素的分子机制。研究的遗传改变包括阳离子胰蛋白酶原（PRSS1）和前羧肽酶A1 （CPA1）的突变。该研究设计将生化和细胞生物学方法与从人类遗传关联研究中获得的数据结合起来，建立一个疾病模型，可以解释突变携带者对慢性胰腺炎的高易感性。我们假设慢性胰腺炎的遗传风险是通过两种独立的病理途径介导的，这两种途径都可能导致腺泡细胞损伤和死亡。在胰蛋白酶依赖的病理途径中，胰蛋白酶原对活性胰蛋白酶的细胞内自激活导致腺泡细胞凋亡；而在错误折叠依赖的病理途径中，错误折叠突变体前酶的保留会引起内质网应激，从而引发凋亡细胞死亡。在下一个资助期内，将研究以下具体目标：(1)阳离子胰蛋白酶原（PRSS1）突变体胞内自激活引起的腺泡细胞损伤；(2)阳离子胰蛋白酶原（PRSS1）突变体的错误折叠和内质网应激(3)CPA1突变与慢性胰腺炎相关的酶和细胞效应分析。

DESCRIPTION (provided by applicant): The broad, long-term objectives of this grant proposal are to understand the molecular mechanisms of genetic risk factors associated with chronic hereditary pancreatitis in humans. The studied genetic alterations include mutations of the cationic trypsinogen (PRSS1) and pro-carboxypeptidase A1 (CPA1). The research design combines biochemical and cell biological approaches with data obtained from human genetic association studies to formulate a disease model that can explain the higher susceptibility of mutation carriers to chronic pancreatitis. We hypothesize that genetic risk in chronic pancreatitis is mediated via two independent pathological pathways, both of which can result in acinar cell damage and death. In the trypsin-dependent pathological pathway intracellular autoactivation of trypsinogen to active trypsin causes acinar cell apoptosis; whereas in the misfolding-dependent pathological pathway retention of misfolded mutant proenzymes induces endoplasmic reticulum stress, which can trigger apoptotic cell death. In the next funding period, the following specific aims will be studied. (1) Acinar cell damage caused by intracellular autoactivation of cationic trypsinogen (PRSS1) mutants; (2) Misfolding of cationic trypsinogen (PRSS1) mutants and endoplasmic reticulum stress (3) Analysis of the enzymatic and cellular effects of novel CPA1 mutations associated with chronic pancreatitis. PUBLIC HEALTH RELEVANCE: The present grant proposal investigates how gene mutations in digestive enzymes cause hereditary pancreatitis, an inherited, progressive inflammatory disease of the pancreas. Results from this study can advance the development of novel diagnostic and therapeutic interventions for all forms of human pancreatitis.