Does Proteotoxicity Contribute to Chronic Pancreatitis in Murine Models of Human Carboxyl Ester Lipase (CEL) Genetic Risk Variants?

在人羧基酯脂肪酶 (CEL) 遗传风险变异小鼠模型中，蛋白质毒性是否会导致慢性胰腺炎？

基本信息

批准号：
10541891
负责人：
MARK E. LOWE
金额：
$ 43.07万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-12-31
项目状态：
已结题

项目摘要

The main goal of this application is to define the biological responses through which carboxyl ester lipase (CEL) genetic mutations increase risk for chronic pancreatitis (CP) in humans. Almost 50% of idiopathic CP in adults and 75% of children with CP have genetic susceptibility driven by mutations in genes encoding pancreatic digestive enzymes. Most of these patients have acute recurrent pancreatitis (ARP) before developing CP. If the episodes of ARP can be stopped, it is likely we can stop the progression to CP. Knowledge about how genetic mutations increase CP risk is critical for developing novel therapies to prevent CP. We will model the process using genetic mutations of CEL, some of which cause autosomal-dominant CP. Our previous work showed that this mutation causes the protein to misfold and accumulate in the cell. The accumulated protein triggers endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). If these responses do not restore protein balance in the ER, inflammatory and cell death pathways are activated. Our overriding hypothesis is that proteins encoded by genetic risk variants of CEL cause pancreatitis by disrupting protein balance in the ER. To address our hypothesis and advance our understanding of the pathophysiology of CP, we will systematically phenotype novel, humanized mouse models of CEL genetic risk variants that cause chronic pancreatitis. We will methodically investigate the cellular responses triggered by expression of pathogenic human genetic variants of CEL utilizing cell culture and mouse models. Finally, we will determine whether chemical chaperones or enhancers of degradative pathways alter the accumulation of mutant CEL. Completion of these studies will establish mutation-induced misfolding of digestive enzymes as a relevant disease mechanism in the pathogenesis of CP and will identify potential therapeutic targets to stop ARP and prevent CP.

该应用的主要目的是定义羧基脂肪酶（CEL）基因突变增加人类慢性胰腺炎（CP）的风险的生物学反应。成年人中几乎50％的特发性CP和75％的CP儿童具有由编码胰腺消化酶突变的遗传敏感性。这些患者大多数在出现CP之前患有急性复发性胰腺炎（ARP）。如果可以停止ARP的发作，那么我们很可能可以停止对CP的进展。关于遗传突变如何增加CP风险的知识对于开发新型疗法以防止CP至关重要。我们将使用CEL的遗传突变对过程进行建模，其中一些引起常染色体主导的CP。我们以前的工作表明，这种突变导致蛋白质折叠并积聚在细胞中。积累的蛋白质触发内质网应激（ER）应激和展开的蛋白质反应（UPR）。如果这些反应不能恢复ER中的蛋白质平衡，则激活炎症和细胞死亡途径。我们的压倒性假设是，由CEL的遗传风险变异编码的蛋白质通过破坏ER中的蛋白质平衡而导致胰腺炎。为了解决我们的假设并提高我们对CP病理生理学的理解，我们将系统地表型新颖，人源化的CEL遗传风险变异的人性化小鼠模型，这些模型会导致慢性胰腺炎。我们将有条不紊地研究通过使用细胞培养和小鼠模型的病原体人遗传变异的表达触发的细胞反应。最后，我们将确定化学伴侣或降解途径的增强子是否会改变突变体CEL的积累。这些研究的完成将建立突变引起的消化酶的错误折叠，作为CP发病机理的相关疾病机制，并将确定潜在的治疗靶标，以阻止ARP并防止CP。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity.

DOI：
10.1016/j.jbc.2021.100661
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Gravdal A;Xiao X;Cnop M;El Jellas K;Johansson S;Njølstad PR;Lowe ME;Johansson BB;Molven A;Fjeld K
通讯作者：
Fjeld K

Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic misfolding.