Targeting Inflammaging with Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF).

使用中脑星形胶质细胞衍生的神经营养因子 (MANF) 靶向炎症。

• 批准号: 9247302
• 负责人: Heinrich Jasper
• 金额: $ 25.26万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247302
• 关键词: Acute; Age; Age Factors; Aging; Aging-Related Process; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Biological Assay; Cell Count; Cell physiology; Cells; Chronic; DNA Damage; Data; Disease; Disease model; Drosophila genus; Epithelial; Exhibits; Functional disorder; Genetic; Genetic study; Health; Hemocytes; Heterozygote; Homeostasis; Immune; Infection; Inflammation; Inflammatory; Inflammatory disease of the intestine; Injection of therapeutic agent; Injury; Intervention; Intestinal Intraepithelial Neoplasia; Longevity; Mediating; Metabolic; Modeling; Mus; Natural regeneration; Outcome Study; Phenotype; Photoreceptors; Proteins; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Role; Serum; Skin; Stem cells; Supplementation; Testing; Therapeutic; Tissues; Trachea; Transgenic Organisms; Translations; Wild Type Mouse; age related; anti aging; base; fly; inflammatory marker; insight; intestinal epithelium; macrophage; monocyte; neurotrophic factor; regenerative; repaired; research study; tissue regeneration; tissue repair; tool

 DESCRIPTION (provided by applicant): Low-level chronic inflammation is a hallmark of aging, and is a promising target for interventions that aim to delay the aging process. An important driver of systemic inflammation is the accumulation of pro-inflammatory (M1) macrophages. M1 Macrophages mediate acute inflammatory episodes after injury or infection, but to resolve inflammation, macrophages have to polarize into and anti-inflammatory (M2) phenotype. In preliminary studies, the applicants have identified Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) as an evolutionarily conserved modulator of immune cell polarization that promotes tissue repair in flies and mice. This function of MANF is required for tissue repair after damage, and can be harnessed to promote tissue regeneration in murine disease models. The applicants further found that serum MANF levels decrease with age, and that MANF deficiency in mice results in phenotypes that are consistent with widespread systemic inflammation. Based on these data, the applicants propose that MANF is a promising, evolutionarily conserved anti-geronic protein that can be used to delay or even reverse age-associated inflammatory phenotypes. To test this hypothesis, the applicants propose studies in flies and mice, pursuing three aims: (i) to characterize the effects of MANF on aging-related phenotypes in Drosophila, (ii) to assess the role of MANF in limiting age- related inflammation in mice, and (iii) to test MANF supplementation as a potential therapy for age-related diseases. The proposed studies will introduce MANF as an immune-modulatory anti-geronic protein that can limit inflammaging and is therapeutically available. A successful outcome of this study will provide a direct avenue toward translation in pro-regenerative and anti-aging therapies.

 描述(由申请人提供)：低水平的慢性炎症是衰老的标志，也是旨在延缓衰老过程的干预措施的一个有希望的目标。全身性炎症的一个重要驱动力是促炎(M1)巨噬细胞的聚集。M1巨噬细胞介导损伤或感染后的急性炎症发作，但为了化解炎症，巨噬细胞必须分化为抗炎(M2)表型。在初步研究中，申请人已确定中脑星形胶质细胞衍生神经营养因子(MANF)是一种进化保守的免疫细胞极化调节剂，可促进苍蝇和小鼠的组织修复。MANF的这一功能是损伤后组织修复所必需的，并可用于在小鼠疾病模型中促进组织再生。申请者进一步发现，血清MANF水平随着年龄的增长而下降，小鼠MANF缺乏会导致与广泛的全身炎症相一致的表型。基于这些数据，申请人认为MANF是一种有希望的、进化上保守的抗老年蛋白，可用于延缓甚至逆转与年龄相关的炎症表型。为了验证这一假设，申请人提出了在果蝇和小鼠身上进行的研究，追求三个目标：(I)表征MANF对果蝇衰老相关表型的影响，(Ii)评估MANF在限制小鼠年龄相关炎症方面的作用，以及(Iii)测试MANF补充剂作为一种潜在的治疗年龄相关疾病的方法。拟议的研究将介绍MANF作为一种免疫调节的抗老年蛋白，可以限制炎症，并可用于治疗。这项研究的成功结果将为促进再生和抗衰老疗法的翻译提供直接途径。