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: 10379376
• 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/10379376
• 关键词: Acute; Address; Affect; Aging; American; Amino Acids; 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; Dysplasia; Enzymes; Epithelial; Epithelial Cells; 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; Immunity; Inflammation; Inflammatory Bowel Diseases; Investigation; Lead; Lipid Peroxidation; Longevity; Longitudinal Studies; 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; Role; Severities; Signal Transduction; Sodium Dextran Sulfate; Source; Spermidine; Spermine; Supplementation; Testing; Tissue Microarray; Tissues; Transgenic Mice; Translating; Translations; Tumor Immunity; Ulcerative Colitis; adduct; base; 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; macrophage; metabolome; murine colitis; 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： 在美国，炎症性肠病（IBD）遭受了超过300万人的困扰，在全球范围内正在增加，并且 导致结肠炎相关的致癌作用（CAC）。我们正在寻找安全的新辅助IBD疗法， 有效且廉价的，也可以降低CAC的风险。精子（SPD）是由多胺产生的 腐腐和精子氧化酶（SMOX）的精子后转换。最近的高影响研究 已经表明，补充SPD可以改善衰老的心血管健康，寿命和生活质量，以及 不会增加癌症的风险。 SPD已在I期临床试验中成功使用。我们有 开发了一种敏感，准确的基于质谱的测定法，用于多胺检测，该测定已增强 我们在这个项目中的功能。我们最近的发现支持使用SPD作为结肠炎的新策略 治疗和预防CAC。长期目标是进一步阐明范围和机制 SPD的保护作用是获得IBD未来人类临床试验所需的见解。我们提出的研究 我们的数据支持：1）患者SMOX的表达是SMOX的表达。 溃疡性结肠炎（UC）和相关发育不良。 2）SMOX缺失的小鼠在结肠中降低了SPD 并加剧硫酸葡萄酸钠（DSS）结肠炎，一个具有UC特征的模型，在 甲氧基烷（AOM）-DSS模型。 3）补充S​​PD可恢复结肠SPD水平并预防结肠炎 和CAC。 4）SPD是用于产生脱氧蛋白合酶产生的氨基酸的底物 （DHP），这是蛋白质翻译的高度特异性形式所必需的，涉及激活 真核翻译起始因子5A（EIF5A）和无偶然的EIF5A（EIF5AHYP）的形成。 DHPS水平 UC患者低。 EIF5AHYP通过SMOX缺失减少，并由SPD在DSS结肠炎和AOM-恢复 DSS诱导的CAC，调节巨噬细胞功能并增强结肠上皮恢复。 5）电泳， 例如Levuglandins（LGS），是脂质过氧化的破坏产物，可导致免疫功能障碍 通过与蛋白质和DNA形成加合物，以及肿瘤风险；我们发现人类UC的加合物增加了 CAC，以及对电生物的特异性清除剂减少了加合物的形成和AOM-DSS中的癌变 模型。重要的是，我们证明了SPD可以清除LGS。我们假设SPD的潜在好处 在结肠炎和癌变中，是由于对免疫反应，上皮功能，非胰岛功能和 电力清除。我们的目的是：1）确定保护的分子和细胞机制 急性和慢性结肠炎模型和CAC中的SPD，包括对转录组/代谢组，自噬的影响 使用具有细胞特异性人SMOX表达的转基因小鼠的免疫细胞与上皮细胞功能。 2）使用与DHP的上皮或粒细胞特异性缺失的小鼠确定SPD是否通过非胰岛作用。 3）确定SPD在减少炎症，基因组不稳定性和 肿瘤发生。我们希望在IBD和CAC预防中提供新的结肠炎治疗策略。