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)

基本信息

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
项目类别：
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

项目摘要

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）严重时可能致命，并且发病率不断增加，导致巨大的医疗负担和费用。目前，除了支持性护理外，AP 没有具体的治疗方法。遗憾的是，针对单个机械上重要步骤的传统策略在临床方面并未取得成功，这可能是由于 AP 中同时激活了多个有害信号通路。此外，肥胖等修饰因素会使引发因素的结果恶化，否则可能会导致轻度 AP，从而增加了额外的复杂性。因此，我们的目的是确定一个参与肥胖期间 AP 启动及其脂毒性加剧的多种机制的靶点。基于其多重作用，我们将 c-Src 确定为这样的靶标，它在药理学上也与人类疾病相关。初步数据：我们发现了 AP 启动过程中 c-Src 在多个层面参与的证据。这些包括高尔基体的 c-Src 依赖性顺行延伸、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、胰腺酶的基底外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 的脂毒性加剧有关。我们发现了 c-Src 参与这种脂毒性加剧的证据。这包括脂肪坏死中 c-Src 表达增加，与脂肪组织中胰脂肪酶量增加相关，同时减少脂肪分解、脂毒性腺泡损伤以及 c-Src 抑制剂改善严重 AP 的情况。 c-Src 表达导致脂滴损失，同时 3T3LI 细胞中脂肪酶量增加，并且在人类脂肪坏死和亚油酸 (LA) 反应中注意到 Src 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 AP 起始及其脂毒性加剧期间的多个步骤。建议：我们建议研究 c-Src 在 AP 引发和脂毒性恶化中的多重作用。这些包括其在调节通过高尔基体的货物运输、胰蛋白酶原激活基底外侧渗漏和腺泡细胞死亡中的作用。基于显示其在 AP 脂毒性恶化中的多种作用的初步数据，我们还计划探索 c-Src 在脂毒性介质（例如 UFA）、生成中的作用以及 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 在腺泡和炎症细胞死亡中的作用，以及腺泡细胞、脂肪细胞产生炎症介质。最后，我们将研究 c-Src 的遗传或药理学抑制是否可以改善轻度和肥胖相关的致死性 AP 的结果。这些新颖的研究可以通过定义单一药理学上可接受的治疗靶点的作用，即 c-Src（目前已批准用于人类使用的药物）在起始和脂毒性加剧期间的多个不同步骤中，为 AP 开辟新的多模式治疗前沿美联社。