Mechanisms of cell death and autophagy in intestinal epithelial cells in inflammation and cancer

炎症和癌症中肠上皮细胞的细胞死亡和自噬机制

• 批准号: 10180908
• 负责人: Jorge Moscat
• 金额: $ 38.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-21 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180908
• 关键词: Address; Anti-Bacterial Agents; Apoptosis; Apoptosis Inhibitor; Autophagocytosis; Biology; Cell Death; Cell Differentiation process; Cell Survival; Cells; Charge; Chronic; Colorectal Cancer; Crohn' s disease; Data; Defect; Disease; Environment; Epithelial Cells; Functional disorder; Homeostasis; Human; Hyperactivity; Immune response; Impairment; Infection prevention; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestinal Cancer; Intestines; MAPK8 gene; Malignant Neoplasms; Mediating; Molecular; Mus; Neoplasms; Nutrient; Organoids; Paneth Cells; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Population; Prevention; Process; Rest; Role; Sampling; Signal Pathway; Signal Transduction; Small Intestines; Testing; Therapeutic; Ulcerative Colitis; Validation; base; colorectal cancer risk; design; dietary; dysbiosis; experimental study; in vivo; inflammatory disease of the intestine; intestinal barrier; intestinal epithelium; intestinal homeostasis; intestinal tumorigenesis; new therapeutic target; novel therapeutics; prevent; stem cells; transcription factor; tumorigenesis

SUMMARY Intestinal epithelial cells (IECs) play an important role as barrier and as cellular factories in charge of absorbing and processing dietary nutrients, as well as the secretion of defense molecules and the orchestration of immune responses. Alterations in the normal function of IECs contribute to pathologies like inflammatory bowel diseases (IBD). Importantly, patients with IBD are at an increased risk for colorectal cancer (CRC), which is one of the most prevalent neoplasias among the US population. Recent studies have shown the critical role of Paneth cell dysfunction in controlling IEC survival and the etiopathogeneis of intestinal inflammation. Therefore, understanding how different signaling cascades control intestinal homeostasis is a fundamental question in biology with potential therapeutic implications for IBD and CRC. We will address these questions in the context of PKCλ/ι. Our preliminary data demonstrate that the selective inactivation of PKCλ/ι in IECs results in the loss of Paneth cells, which provokes the break of the intestinal barrier, dysbiosis, intestinal inflammation and increased tumorigenesis. Importantly, PKCλ/ι expression decreases with progression in CD and it predicts poor survival in CRC. Of note, this Paneth cell defect is associated with increased crypt apoptosis, JNK activity and autophagy in PKCλ/ι-deficient IECs. Our hypothesis is that PKCλ/ι is an essential regulator of autophagy and cell death in intestinal cell homeostasis and inflammation-driven tumorigenesis. In this proposal we will address the following fundamental questions: (1) What is the role in vivo of JNK activation by PKCλ/ι deficiency in increased apoptosis of IECs and intestinal inflammation and tumorigenesis? (2) What are the mechanisms whereby PKCλ/ι inhibits JNK activity? (3) Is enhanced autophagy in PKCλ/ι-deficient IECs a survival mechanism in vivo to antagonize the increased JNK and apoptosis promoted by the loss of PKCλ/ι and to prevent intestinal inflammation and tumorigenesis? (4) What are the mechanisms whereby PKCλ/ι represses autophagy? Questions 1 and 2 will be answered by the experiments described in Aim 1; and questions 3 and 4 will be answered by the experiments described in Aim 2. This proposal will unveil a new paradigm whereby PKCλ/ι controls IEC apoptosis and autophagy and their role in intestinal homeostasis and inflammation-driven tumorigenesis, opening possibilities for new therapies.

概括 肠上皮细胞（IEC）作为屏障和负责吸收的细胞工厂发挥着重要作用 和处理膳食营养素，以及防御分子的分泌和免疫的协调 IEC 正常功能的改变会导致炎症性肠病等疾病。 (IBD) 重要的是，IBD 患者患结直肠癌 (CRC) 的风险增加，结直肠癌是癌症之一。 最近的研究表明潘氏细胞在美国人群中最常见的肿瘤中发挥着关键作用。 控制 IEC 存活和肠道炎症病因的功能障碍。 了解不同的信号级联如何控制肠道稳态是一个基本问题 对 IBD 和 CRC 具有潜在治疗意义的生物学问题我们将在上下文中解决这些问题。 我们的初步数据表明，IEC 中 PKCλ/ι 的选择性失活会导致损失。 潘氏细胞，会引起肠道屏障的破坏、菌群失调、肠道炎症和 重要的是，PKCλ/ι 表达随着 CD 的进展而降低，并且它预测较差。 值得注意的是，这种潘氏细胞缺陷与隐窝细胞凋亡、JNK 活性和 PKCλ/ι 缺陷 IEC 中的自噬 我们的假设是 PKCλ/ι 是自噬和自噬的重要调节因子。 在本提案中，我们将讨论肠道细胞稳态中的细胞死亡和炎症驱动的肿瘤发生。 以下基本问题：(1) PKCλ/ι 缺陷导致的 JNK 激活在体内的作用是什么？ IECs凋亡增加与肠道炎症和肿瘤发生有关（2）其机制是什么？ 因此 PKCλ/ι 抑制 JNK 活性？ (3) PKCλ/ι 缺陷的 IEC 中自噬增强是一种生存吗？ 体内机制拮抗因 PKCλ/ι 缺失而促进的 JNK 增加和细胞凋亡， 预防肠道炎症和肿瘤发生？ (4) PKCλ/ι 抑制的机制是什么？ 问题 1 和 2 将通过目标 1 和问题 3 和 4 中描述的实验来回答； 将通过目标 2 中描述的实验来回答。该提案将揭示一种新的范式，其中 PKCλ/ι 控制 IEC 细胞凋亡和自噬及其在肠道稳态和炎症驱动中的作用 肿瘤发生，为新疗法开辟了可能性。