Role of Neurogenic Inflammation in Pancreatic Cancer

神经源性炎症在胰腺癌中的作用

• 批准号: 8559041
• 负责人: BRIAN M DAVIS
• 金额: $ 40.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8559041
• 关键词: Ablation; Affect; Afferent Neurons; Appearance; Attenuated; Automobile Driving; Blood; Blood Circulation; Brain-Derived Neurotrophic Factor; Calcitonin Gene-Related Peptide; Cells; Clinical; Conditioned Culture Media; Data; Development; Diagnosis; Disease; Disease Progression; Distant; Edema; Electrophysiology (science); Epithelial Cells; Exposure to; Fiber; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Glutamates; Growth Factor; Human; Hypersensitivity; Immune system; Individual; Inflammation; Inflammatory; Label; Laboratories; Lead; Lesion; Link; Liver; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Methodology; Methods; Modeling; Mus; Nature; Nerve Growth Factor Receptors; Nerve Growth Factors; Nervous system structure; Neurogenic Inflammation; Neurons; Nodose Ganglion; Organ; Pancreas; Pancreatectomy; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Physicians; Play; Premalignant; Process; Production; Property; Risk; Role; Sensory; Signal Transduction; Staging; Substance P; TRP channel; Testing; Time; Tissues; United States; Up-Regulation; Western Blotting; acute pancreatitis; afferent nerve; base; chronic pancreatitis; cytokine; glial cell-line derived neurotrophic factor; high risk; mouse model; neurotrophic factor; neutralizing antibody; novel; pancreatic neoplasm; patch clamp; prevent; prophylactic; public health relevance; relating to nervous system; research study; response; spinal nerve posterior root; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC), like many cancers, has a major inflammatory component that is integral to disease progression. In humans, patients with familial chronic pancreatitis (CP) have a 53-fold increase in their risk for PDAC [92] and 40% go on to develop pancreatic cancer [63]. The link between CP and PDAC is so strong that physicians often recommend prophylactic pancreatectomy for patients with severe CP. The mechanistic link between pancreatic inflammation and cancer is not known. However, studies by our laboratories and others indicate that inflammation accelerates the disease, driving maturation of precancerous lesions into frank cancer [40, 41]. Furthermore, in a genetically engineered mouse model (GEM) of PDAC, pancreatic inflammation increased dissemination of pancreatic cells into the blood and liver [78]. Experiments in our labs show that pancreatic inflammation can be regulated by the nervous system. The importance of "neurogenic inflammation" is supported by studies that show ablation or silencing of pancreatic afferents attenuates/prevents acute and chronic pancreatitis [45, 67, 81, 82]. PDAC converts the pancreas into a tissue that produces pathological levels of neurotrophic factors that cause hypersensitivity and sprouting of sensory neuron terminals and this likely underlie disease-related neurogenic inflammation. Importantly, preliminary data from our lab indicate that growth factor upregulation begins early in the disease process, even before the appearance of frank cancer (Preliminary Data). These observations in combination with the role that inflammation appears to play in progression of PDAC leads to the central hypothesis of this application: PDAC-generated neurotrophic factors induce neurogenic inflammation that drives PDAC progression. This hypothesis will be tested in the following specific aims: Aim 1: Determine the effect of PDAC-produced neurotrophic factors on pancreatic afferents (dorsal root and nodose ganglion neurons) and whether blocking these growth factors attenuates the release of neurogenic inflammatory molecules. Aim 2: Determine the contribution of neurogenic inflammation to PDAC progression and tumor growth. These studies will directly test the role of the nervous system in PDAC. Three different methodologies will be tested for their ability to block neurogenic inflammation and slow/halt disease progression. Each of these methods is either currently available or in development for use in the clinical setting. If successful, any of these approaches could be used for patients with high-risk for PDAC or those in which the disease is already diagnosed.

描述（由申请人提供）：像许多癌症一样，胰腺导管腺癌（PDAC）具有主要的炎症成分，是疾病进展不可或缺的。在人类中，家族性慢性胰腺炎（CP）患者的PDAC风险增加了53倍[92]，40％继续发展胰腺癌[63]。 CP和PDAC之间的联系非常牢固，以至于医生通常建议患有严重CP患者的预防性胰腺切除术。胰腺炎症与癌症之间的机械联系尚不清楚。但是，我们的实验室和其他研究表明，炎症加速了疾病，将癌前病变成熟到弗兰克癌症中[40，41]。此外，在PDAC的基因工程小鼠模型（GEM）中，胰腺炎症增加了胰腺细胞在血液和肝脏中的传播[78]。 我们实验室中的实验表明，胰腺炎症可以由神经系统调节。 “神经源性炎症”的重要性得到了研究表明胰腺传入的消融或沉默的研究支持/阻止急性和慢性胰腺炎[45，67，81，82]。 PDAC将胰腺转化为一种组织，该组织产生病理水平的神经营养因素，导致感觉神经元末端的超敏反应和发芽，并且这种可能是与疾病相关的神经源性炎症的基础。重要的是，我们实验室的初步数据表明，即使在Frank Cancer出现之前，生长因子上调也开始于疾病过程的早期（初步数据）。这些观察结果与炎症在PDAC进展中起着作用的作用，从而导致了该应用的中心假设：PDAC生成的神经营养因子诱导神经源性炎症，从而驱动PDAC进展。该假设将在以下特定目的中进行检验： AIM 1：确定PDAC产生的神经营养因子对胰腺传入（背根和淋巴结神经节神经元）的影响，以及阻断这些生长因子是否会减轻神经源性炎症分子的释放。 目标2：确定神经源性炎症对PDAC进展和肿瘤生长的贡献。 这些研究将直接测试神经系统在PDAC中的作用。将测试三种不同的方法，以阻止神经源性炎症和缓慢/停止疾病进展的能力。这些方法中的每一种都可以在临床环境中可用，要么在开发中用于开发。如果成功的话，这些方法中的任何一种可用于患者 PDAC的高风险或已经诊断出疾病的高危。