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

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，导致重大的医疗负担和费用。目前，除支持治疗外，AP没有特异性治疗。不幸的是，针对单一机制重要步骤的传统策略在临床方面并未取得成功，这可能是由于在AP中同时激活了多种有害的信号通路。此外，肥胖等调节剂会使原本可能导致轻度AP的引发物的结果恶化，从而增加了额外的复杂性。因此，我们旨在确定一个靶标，该靶标可能涉及肥胖期间AP启动及其脂毒性加剧的多种机制。基于其多重作用，我们确定了c-Src作为这样一个靶点，它在药理学上也与人类疾病相关。初步数据：我们发现在AP发生过程中，c-Src在多个层面参与的证据。其中包括c-Src依赖性高尔基体顺行延伸、胰糜蛋白酶通过高尔基体转运、胰蛋白酶原激活、f -肌动蛋白重塑、胰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的脂毒性恶化有关。我们发现了c-Src参与脂毒性恶化的证据。这包括脂肪坏死中c-Src的表达增加，与脂肪组织中胰脂肪酶数量增加有关，同时脂肪分解、脂毒性腺泡损伤减少，以及c-Src抑制剂改善严重AP。c-Src表达导致脂滴损失，同时3T3LI细胞中脂肪酶数量增加，Src激活在人类脂肪坏死和亚油酸（LA）反应中被注意到，这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启动及其脂毒性恶化的多个步骤。建议：我们建议研究c-Src在AP的起始和脂毒性恶化中的多重作用，包括其在通过高尔基体调节货物运输、胰蛋白酶原激活基底外侧渗漏和腺泡细胞死亡中的作用。基于初步数据显示其在AP脂毒性加重中的多重作用，我们还计划探索c-Src在脂毒性介质（如UFA）的产生中的作用，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在腺泡细胞和炎症细胞死亡中的作用

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.