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）可能在严重且发病率增加时可能致命，导致巨大的医疗保健负担和成本。目前，除了支持护理外，AP没有具体的疗法。不幸的是，靶向单个机械上重要步骤的常规策略在临床方面没有成功，这可能是由于AP中同时激活的多个有害信号通路。此外，像肥胖症这样的修饰符会使引发剂的结果恶化，否则可能会导致轻度的AP，从而增加了额外的复杂性。因此，我们旨在确定将涉及多种AP启动机制及其在肥胖期间的脂肪毒性加剧的靶标。根据其多重作用，我们将C-SRC确定为这样的靶标，这也与人类疾病有关。初步数据：我们发现C-SRC在AP启动过程中众多级别的参与证据。其中包括高尔基体的C-SRC依赖性前结束，通过高尔基体运输胰凝乳蛋白酶，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。有力的证据表明，在肥胖期间AP的脂蛋白毒性加剧中，不饱和脂肪酸（UFA）。我们发现了C-SRC参与这种脂肪毒性加重的证明。这包括在脂肪坏死中增加C-SRC的表达，与脂肪组织中胰腺脂肪酶量增加以及脂肪分解，脂肪毒性腺泡损伤的减少以及C-SRC抑制剂在严重AP中的改善有关。 C-SRC的表达进一步支持了脂质液滴的损失，以及3T3LI细胞中的脂肪酶量的增加，并且在人类脂肪坏死和对亚油酸（LA）的响应中指出了SRC激活。因此，我们假设C-SRC是AP中的一个治疗靶标，因为它在AP启动过程中参与了多个步骤及其脂肪毒性加重。提案：我们建议研究C-SRC在AP的启动和脂肪毒性加剧中的多重作用。其中包括其在通过高尔基体，胰蛋白酶原激活的基底外侧泄漏和腺泡细胞死亡中调节货物运输方面的作用。根据显示其在AP的脂蛋白毒性加剧中的多重作用的初步数据，我们还计划探索C-SRC在脂肪毒性介质（例如UFA），生成以及C-SRC中的作用，以及C-SRC如何进一步调节这些脂蛋白毒性介体对腺泡和炎症反应。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的遗传或药理抑制是否可以改善与致死性AP相关的轻度和肥胖症的预后。这些新的研究可以通过确定单个药理学上可融合的治疗靶点的作用，即在启动时以多个不同的步骤和AP的Lipototoxic Aperbation在多个不同的步骤中，可以为AP开辟新的多模式治疗前端。