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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.

本应用程序的主要目的是确定羧基酯脂肪酶（CEL）基因突变增加人类慢性胰腺炎（CP）风险的生物学反应。近50%的成人特发性CP患者和75%的儿童CP患者具有由编码胰腺消化酶的基因突变驱动的遗传易感性。大多数患者有急性复发性胰腺炎(ARP)之前开发CP。如果ARP的情节可以停止了,可能我们可以停止CP的发展。知识CP基因突变如何增加风险是至关重要的新的治疗方法来防止CP。我们将过程模型使用基因突变的玻璃纸,其中一些导致常染色体显性CP。我们以前的工作表明,这种突变导致细胞中的蛋白质错误折叠和积累。积累的蛋白质触发内质网（ER）应激和未折叠蛋白反应（UPR）。如果这些反应不能恢复内质网中的蛋白质平衡，炎症和细胞死亡途径就会被激活。我们最重要的假设是，由CEL遗传风险变异体编码的蛋白质通过破坏内质网中的蛋白质平衡而导致胰腺炎。为了证明我们的假设并推进我们对CP病理生理学的理解，我们将系统地对导致慢性胰腺炎的CEL遗传风险变异的新型人源化小鼠模型进行表型分析。我们将利用细胞培养和小鼠模型系统地研究CEL致病性人类遗传变异表达引发的细胞反应。最后，我们将确定降解途径的化学伴侣或增强剂是否会改变突变型CEL的积累。这些研究的完成将确立突变诱导的消化酶错误折叠作为CP发病机制的相关疾病机制，并将确定阻止ARP和预防CP的潜在治疗靶点。

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）

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

DOI：
10.1002/humu.24105
发表时间：
2020-11
期刊：
Human mutation
影响因子：
3.9
作者：
Cassidy BM;Zino S;Fjeld K;Molven A;Lowe ME;Xiao X
通讯作者：
Xiao X

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