Spermidine as a New Therapy for Colitis and Chemopreventive for Colitis-associated Carcinogenesis

亚精胺作为结肠炎的新疗法和结肠炎相关癌的化学预防

• 批准号: 10579252
• 负责人: Keith T. Wilson
• 金额: $ 67.54万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-31 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579252
• 关键词: Acute; Address; Affect; Aging; American; Amino Acids; Animals; Arginine; Autophagocytosis; Azoxymethane; Back; Biological; Biological Assay; Carcinoma; Cell Line; Cell physiology; Cells; Chemopreventive Agent; Chronic; Clinical; Clinical Trials; Colitis; Colon; Colonic inflammation; Crohn' s disease; DNA; Data; Detection; Drug Metabolic Detoxication; Dysplasia; Enzymes; Epithelial Cells; Epithelium; Eukaryotic Initiation Factors; Exhibits; Future; Generations; Genetically Engineered Mouse; Genomic Instability; Genomics; Goals; High Pressure Liquid Chromatography; Histologic; Human; Immune; Immune System Diseases; Immune response; Immune system; Inflammation; Inflammatory Bowel Diseases; Investigation; Lipid Peroxidation; Longevity; Longitudinal Studies; Macrophage; Malignant Neoplasms; Mammalian Cell; Mass Spectrum Analysis; Measurement; Mediating; Metabolism; Methodology; Methods; Microbe; Modeling; Molecular; Mucosal Immune Responses; Mus; Myelogenous; Myeloid Cells; Natural Products; Neoplasms; Oncogenic; Ornithine; Ornithine Decarboxylase; Oxazolone; Patients; Persons; Phase I Clinical Trials; Plants; Polyamines; Prevalence; Prevention; Proteins; Public Health; Publishing; Putrescine; Quality of life; Reporting; Risk; Risk Reduction; Role; Severities; Signal Transduction; Sodium Dextran Sulfate; Source; Spermidine; Spermine; Supplementation; Testing; Tissue Microarray; Tissues; Transgenic Mice; Translating; Translations; Tumor Immunity; Ulcerative Colitis; adduct; cancer chemoprevention; cancer prevention; cancer risk; carcinogenesis; cardiovascular health; colon carcinogenesis; colorectal cancer prevention; deoxyhypusine synthase; dextran sulfate sodium induced colitis; drinking water; healing; hypusine; immunoregulation; improved; in vivo; insight; liquid chromatography mass spectrometry; mRNA Expression; metabolome; neoplastic; novel; novel therapeutics; overexpression; polyamine oxidase; protective effect; response; transcriptome; treatment strategy; tumor; tumorigenesis

SUMMARY: Inflammatory bowel disease (IBD) afflicts over three million people in the USA, is increasing worldwide, and leads to colitis-associated carcinogenesis (CAC). We are seeking new adjunctive IBD therapies that are safe, effective, and inexpensive that could also reduce risk for CAC. Spermidine (Spd) is a polyamine generated from putrescine and from back-conversion of spermine by spermine oxidase (SMOX). Recent high-impact studies have shown that Spd supplementation improves cardiovascular health, longevity and quality of life in aging, and does not increase the risk for cancer. Spd has been used successfully in Phase I clinical trials. We have developed a sensitive, accurate mass spectrometry-based assay for polyamine detection, which has enhanced our capabilities for this project. Our recent discoveries support the use of Spd as a new strategy for colitis treatment and CAC prevention. The long-term goal is to further elucidate the scope and mechanisms underlying the protective effect of Spd to gain insights needed for future human clinical trials in IBD. Our proposed studies are supported by our data indicating that: 1) Expression of SMOX, a key source of Spd, is reduced in patients with ulcerative colitis (UC) and associated dysplasia. 2) Mice with Smox deletion have reduced Spd in the colon and exacerbation of both dextran sulfate sodium (DSS) colitis, a model with features of UC, and CAC in the azoxymethane (AOM)-DSS model. 3) Spd supplementation restores colon Spd levels and protects against colitis and CAC. 4) Spd is the substrate for generation of hypusine, an amino acid produced by deoxyhypusine synthase (DHPS), which is required for a highly specific form of protein translation, hypusination, involving activation of eukaryotic translation initiation factor 5A (EIF5A) and formation of hypusinated EIF5A (EIF5AHyp). DHPS levels are low in UC patients. EIF5AHyp is reduced by Smox deletion and restored by Spd during DSS colitis and AOM- DSS-induced CAC, regulates macrophage function, and enhances colonic epithelial restitution. 5) Electrophiles, such as levuglandins (LGs), are damaging products of lipid peroxidation that can lead to immune dysfunction and neoplastic risk by forming adducts with proteins and DNA; we found increased adducts in human UC and CAC, and a specific scavenger of electrophiles reduced adduct formation and carcinogenesis in the AOM-DSS model. Importantly, we demonstrate that Spd can scavenge LGs. We hypothesize that potential benefits of Spd in colitis and carcinogenesis are due to effects on immune responses, epithelial function, hypusination, and electrophile scavenging. Our Aims are: 1) To determine the molecular and cellular mechanisms of protection by Spd in acute and chronic colitis models and CAC, including effects on the transcriptome/metabolome, autophagy, and immune cell versus epithelial cell function using transgenic mice with cell-specific human SMOX expression. 2) To determine if Spd acts through hypusination, using mice with epithelial- or myeloid-specific deletion of Dhps. 3) To determine the role of Spd as an electrophile scavenger in reducing inflammation, genomic instability, and tumorigenesis. We expect to deliver a new strategy for colitis treatment in IBD and for CAC prevention.

概括： 炎症性肠病 (IBD) 在美国影响着超过 300 万人，并且在全球范围内呈上升趋势，并且 导致结肠炎相关癌变（CAC）。我们正在寻找安全的新的 IBD 辅助疗法， 有效且廉价，还可以降低 CAC 风险。亚精胺 (Spd) 是一种多胺，由 腐胺和精胺氧化酶 (SMOX) 反向转化的精胺。最近的高影响力研究 研究表明，补充 Spd 可以改善心血管健康、长寿和老年生活质量，并且 不会增加患癌症的风险。 Spd已成功用于I期临床试验。我们有 开发了一种灵敏、准确的基于质谱的多胺检测方法，该方法增强了 我们对该项目的能力。我们最近的发现支持使用 Spd 作为结肠炎的新策略 治疗和 CAC 预防。长期目标是进一步阐明其背后的范围和机制 Spd 的保护作用，以获得未来 IBD 人体临床试验所需的见解。我们提出的研究 我们的数据支持了这一点，表明：1）患者中 Spd 的关键来源 SMOX 的表达减少 患有溃疡性结肠炎（UC）和相关的发育不良。 2) Smox缺失的小鼠结肠中的Spd降低 右旋糖酐硫酸钠 (DSS) 结肠炎（一种具有 UC 特征的模型）和 CAC 的恶化 氧化偶氮甲烷 (AOM)-DSS 模型。 3) 补充 Spd 可恢复结肠 Spd 水平并预防结肠炎 和CAC。 4) Spd 是产生 hypusine 的底物，hypusine 是一种由脱氧hypusine 合酶产生的氨基酸 （DHPS），这是高度特异性的蛋白质翻译形式（hypusination）所必需的，涉及激活 真核翻译起始因子 5A (EIF5A) 和 hypuslated EIF5A (EIF5AHyp) 的形成。 DHPS水平 UC 患者中较低。在 DSS 结肠炎和 AOM 期间，EIF5AHyp 通过 Smox 缺失而减少，并通过 Spd 恢复 DSS 诱导 CAC，调节巨噬细胞功能，增强结肠上皮恢复。 5) 亲电子试剂， 例如 levuglandins (LG)，是脂质过氧化的破坏性产物，可导致免疫功能障碍 与蛋白质和 DNA 形成加合物而导致肿瘤风险；我们发现人类 UC 中的加合物增加， CAC 和一种特定的亲电子清除剂可减少 AOM-DSS 中的加合物形成和致癌作用 模型。重要的是，我们证明了 Spd 可以清除 LG。我们假设 Spd 的潜在好处 结肠炎和癌变是由于对免疫反应、上皮功能、催眠作用和 亲电子清除。我们的目标是： 1) 确定分子和细胞的保护机制 急性和慢性结肠炎模型和 CAC 中的 Spd，包括对转录组/代谢组、自噬、 使用具有细胞特异性人 SMOX 表达的转基因小鼠来研究免疫细胞与上皮细胞的功能。 2) 使用具有上皮或骨髓特异性 Dhps 缺失的小鼠来确定 Spd 是否通过 hypusination 发挥作用。 3) 确定 Spd 作为亲电子清除剂在减少炎症、基因组不稳定性和 肿瘤发生。我们期望为 IBD 结肠炎治疗和 CAC 预防提供新策略。