Src and its Multiple Adverse Roles Targeted (SMART) in Acute Pancreatitis

Src 及其在急性胰腺炎中的靶向多重不良作用 (SMART)

• 批准号: 9210618
• 负责人: Vijay Prem Singh
• 金额: $ 37.35万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210618
• 关键词: Acinar Cell; Acinus organ component; Actins; Adipocytes; Adipose tissue; Affect; Agreement; Amylases; Apical; Biological; Caerulein; Cathepsins B; Cell Death; Cells; Cessation of life; Clinical; Dasatinib; Data; Debridement; Diet; Drug Targeting; Enzyme Precursors; Enzymes; Etiology; Extravasation; F-Actin; Fat necrosis; Fatty Acids; Fatty acid glycerol esters; Generations; Genetic; Golgi Apparatus; Healthcare; Hospitalization; Human; Incidence; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Kidney; Learning; Linoleic Acids; Lipase; Lipids; Lipolysis; Liquid substance; Lung; Mediating; Mediator of activation protein; Messenger RNA; Mild obesity; Mus; Necrosis; Obese Mice; Obesity; Organ failure; Outcome; Pancreas; Pancreatic enzyme; Patients; Pharmaceutical Preparations; Pharmacology; Rodent; Role; SRC gene; Serine Protease; Serum; Severities; Signal Pathway; Signal Transduction; Supportive care; Testing; Therapeutic; Thinness; Treatment Efficacy; Trypsin; Trypsinogen; United States; Unsaturated Fatty Acids; Visceral; Zymogen Granules; acute pancreatitis; base; care burden; cell injury; chymotrypsin; cost; cytokine; frontier; human disease; improved; improved outcome; inhibitor/antagonist; mortality; multimodality; novel; overexpression; prevent; protein-tyrosine kinase c-src; public health relevance; response; therapeutic evaluation; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Acute Pancreatitis (AP) is potentially lethal when severe and is increasing in incidence, resulting in significant health care burden and costs. Currently AP has no specific therapy apart from supportive care. The conventional strategy of targeting a single mechanistically important step has unfortunately not been successful on the clinical front, likely due to the multiple deleterious signaling pathways simultaneously activated in AP. Additionally, modifiers like obesity worsen outcomes from an initiator which may otherwise cause mild AP, adding an additional layer of complexity. We thus aimed at identifying a target that would be involved in multiple mechanisms of AP initiation and its lipotoxic exacerbation during obesity. Based on its multiple roles, we identified c-Src as such a target, which also is pharmacologically relevant to human disease. PRELIMINARY DATA: We found evidence of c-Src's involvement at numerous levels during AP initiation. These included c-Src dependent antegrade extension of the Golgi, trafficking of chymotrypsin through the Golgi, trypsinogen activation, F-actin remodeling, basolateral release of pancreatic enzymes and acinar cell death. Strong evidence implicates unsaturated fatty acids (UFA) in the lipotoxic exacerbation of AP during obesity. We found proof of c-Src's involvement in this lipotoxic exacerbation. This included increased expression of c-Src in fat necrosis, associated with increased pancreatic lipase amounts in adipose tissue, along with a reduction in lipolysis, lipotoxic acinar injury, and improvement in severe AP by inhibitors of c-Src. This is further supported by c-Src expression causing a loss of lipid droplets, along with increasing lipase amounts in 3T3LI cells, and Src activation being noted in human fat necrosis and in response to linoleic acid (LA). We therefore hypothesize that c-Src is a therapeutic target in AP since it is involved in multiple steps during AP initiation and its lipotoxic exacerbation. PROPOSAL: We propose to study the multiple roles of c-Src in the initiation and lipotoxic exacerbation of AP. These include its role in regulating trafficking of cargo through the Golgi, trypsinogen activation basolateral leakage and acinar cell death. Based on preliminary data showing its multiple roles in lipotoxic exacerbation of AP, we also plan to explore the role of c-Src in lipotoxic mediator (e.g. UFA), generation and how c-Src further regulates the acinar and inflammatory response to these lipotoxic mediators. This includes c-Src's role in acinar and inflammatory cell death, and in the generation of inflammatory mediators by acinar cells, adipocytes. Lastly, we will study whether genetic or pharmacologic inhibition of c-Src improves outcomes in both mild and obesity associated lethal AP. These novel studies could open a new multimodal therapeutic frontier for AP by defining the role of a single pharmacologically amenable therapeutic target, i.e. c-Src (for which there are drugs currently approved for human use) in multiple distinct steps during the initiation and lipotoxic exacerbation of AP.

描述(由申请人提供)：急性胰腺炎(AP)在严重时具有潜在的致命性，并且发病率正在增加，导致巨大的医疗负担和成本。目前，除支持性治疗外，AP尚无特效治疗方法。不幸的是，针对单个机械重要步骤的传统策略在临床方面并不成功，可能是因为AP中同时激活了多个有害的信号通路。此外，肥胖等修饰物会恶化发起者的结果，否则可能会导致轻度AP，增加了额外的一层复杂性。因此，我们的目标是确定一个靶点，该靶点将参与AP的启动及其在肥胖过程中脂毒性加剧的多种机制。基于其多重作用，我们将c-Src确定为这样一个靶点，它在药理上也与人类疾病相关。初步数据：我们发现了在AP启动过程中c-Src在多个水平上参与的证据。这些包括c-Src依赖的高尔基体顺行延伸、胰凝乳蛋白酶通过高尔基体的运输、胰蛋白酶原激活、F-肌动蛋白重塑、胰酶的基侧释放和腺泡细胞死亡。强有力的证据表明，不饱和脂肪酸(UFA)与肥胖期间AP的脂毒性加重有关。我们发现了c-Src参与这种脂毒性加重的证据。这包括c-Src在脂肪坏死中的表达增加，与脂肪组织中胰腺脂肪酶数量的增加相关，以及脂肪分解、脂毒性腺泡损伤的减少，以及c-Src抑制剂对严重AP的改善。C-Src的表达导致脂滴的丢失，以及3T3LI细胞中脂肪酶数量的增加，以及在人类脂肪坏死和对亚油酸(LA)的反应中发现Src的激活，进一步支持了这一点。因此，我们假设c-Src是AP的治疗靶点，因为它参与了AP启动及其脂毒性加重的多个步骤。建议：我们建议研究c-Src在AP的启动和脂毒性加重中的多重作用。这些包括它在调节通过高尔基体运输货物、胰酶原激活、基底面渗漏和腺泡细胞死亡中的作用。根据初步数据显示其在AP的脂毒性加重中的多种作用，我们还计划探讨c-Src在脂毒性介质(如不饱和脂肪酸)中的作用，以及c-Src如何进一步调节对这些脂毒性介质的腺泡和炎症反应。这包括c-Src在腺泡和炎性细胞死亡中的作用，以及在 腺泡细胞、脂肪细胞产生炎症介质。最后，我们将研究c-Src的遗传或药物抑制是否能改善轻度和肥胖相关的致死性AP的预后。这些新颖的研究可能为AP开辟一个新的多模式治疗前沿，通过定义单一的药理上可服从的治疗靶点，即c-Src(目前已批准用于人类使用的药物)在AP的启动和脂毒性加重过程中的多个不同步骤中的作用。