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DHA attenuates Inflammatory Responses Through Altering RAGE Signaling

DHA 通过改变 RAGE 信号传导减弱炎症反应

基本信息

批准号：
8867143
负责人：
Lynette Kay Rogers
金额：
$ 34.57万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8867143
关键词：
Acids Advanced Glycosylation End Products Affect Affinity Alveolar Macrophages Anti-Inflammatory Agents Anti-inflammatory Attenuated Binding Blood specimen Bronchopulmonary Dysplasia Chemotaxis Development Diagnosis Disease Docosahexaenoic Acids Dose Endothelial Cells Epithelial Epithelial Cells Event Exhibits Extracellular Domain Fetus Genetic Transcription Goals Growth Health Human Human Milk Hyperoxia Infant Inflammation Inflammatory Inflammatory Response Injury Knockout Mice Leukocyte Chemotaxis Leukocytes Ligands Link Lung Measures Mediating Medical Membrane Milk Milk Banks Molecular Mothers Mus Neurologic Newborn Infant Oxygen Parenteral Nutrition Pattern Phospholipids Plasma Play Premature Birth Premature Infant Production Property Receptor Signaling Risk Role Severities Signal Pathway Signal Transduction Specificity Structure Supplementation Testing Third Pregnancy Trimester Time Tissues Type I Epithelial Receptor Cell Vitamins Woman cell type chemokine clinical investigation cytokine improved life-sustaining therapy long chain fatty acid lung development lung injury monocyte mouse model premature prenatal protein expression receptor receptor binding receptor-mediated signaling respiratory

项目摘要

DESCRIPTION (provided by applicant): Docosahexaenoic acid (DHA) is a long chain fatty acid that exhibits anti-inflammatory and immuno-modulating properties. Although the mechanisms involved are not completely understood, the anti-inflammatory properties of long chain fatty acids are thought to include effects on signaling pathways resulting in modified gene transcription. To date, a specific high affinity receptor for DHA has not been identified however DHA-mediated decreases in cytokine and chemokine production are likely due to receptor related mechanisms. Receptor for Advanced Glycation End Products (RAGE) is a "Damage Associated Molecular Pattern" receptor and, as such, is able to engage classes of unrelated molecules using tertiary structure for ligand recognition. RAGE is highly expressed in lung; specifically epithelial type I cells, endothelial cells, and alveolar macrophages. RAGE protein expression is increased in the lungs of mice exposed to hyperoxia, and the increase is related to the severity of injury. Furthermore, RAGE knockout mice are protected from hyperoxic lung injury, indicating that RAGE-mediated events play a role in the development of lung injury. DHA is preferentially accreted by the third trimester human fetus to aid the maturation of neurological tissues. Extremely preterm infants are born prior to this accretion and are often not provided "pre-formed" DHA in parenteral nutrition or receive low levels in milk from human milk banks. In addition, prematurely born infants often require life-sustaining therapies, including ventilatory support and high concentrations of oxygen and are at risk for inflammation associated with hyperoxic lung injury. Bronchopulmonary Dysplasia (BPD) is one of the most common diseases of prematurity and is closely linked to both maternal and infant inflammatory responses. Infants diagnosed with BPD have decreased lung alveolarization and often require respiratory support for a prolonged period of time. Furthermore, infants with BPD often exhibit delayed neurological development and are at risk for other medical problems that further impair their overall health. The central hypothesis is that DHA attenuates hyperoxia- induced lung injury by decreasing leukocyte chemotaxis, through altering RAGE expression and signaling pathways. Aim 1 will test the hypothesis that DHA supplementation decreases inflammation through the modulation of soluble RAGE (sRAGE) levels and activity. sRAGE is generated by proteolytic cleavage of the extracellular domain of membrane-bound RAGE (mRAGE). sRAGE can enhance chemotaxis and promote maturation and differentiation of monocytes. This aim will investigate the mechanisms by which DHA decreases sRAGE levels in the context of hyperoxia exposure. Aim 2 will test the hypothesis that DHA supplementation alters RAGE-mediated signaling pathways. DHA can propagate or antagonize receptor- mediated signaling by either directly binding to the ligand domain or influencing the ability of ligand to bind or activate the receptor. This aim will investigate the mechanisms by which DHA diminishes intracellular pro- inflammatory signaling. Aim 3 will test the hypothesis that DHA supplementation to lactating women will provide DHA to preterm infants and result in decreased sRAGE expression and inflammatory responses in both the mother and the infant. These studies will investigate the influence of DHA on sRAGE levels in the context of preterm birth. The studies outlined in this proposal will combine an established newborn mouse model of hyperoxia exposure and arrested lung development with clinical investigations in preterm human infants to investigate the mechanisms by which DHA decreases inflammation and improves lung growth.

描述(申请人提供)：二十二碳六烯酸(DHA)是一种长链脂肪酸，具有抗炎和免疫调节特性。尽管相关的机制还不完全清楚，但长链脂肪酸的抗炎特性被认为包括对导致基因转录修饰的信号通路的影响。到目前为止，DHA的特异性高亲和力受体还没有确定，但DHA介导的细胞因子和趋化因子产生的减少可能是由于受体相关的机制。高级糖基化终产物受体(RAGE)是一种“损伤相关的分子模式”受体，因此能够利用三级结构结合不相关的分子进行配体识别。RAGE在肺中高度表达，尤其是I型上皮细胞、内皮细胞和肺泡巨噬细胞。高氧暴露小鼠肺组织RAGE蛋白表达增加，且这种增加与损伤的严重程度有关。此外，RAGE基因敲除小鼠对高氧性肺损伤具有保护作用，这表明RAGE介导的事件在肺损伤的发生发展中发挥了作用。DHA优先由妊娠晚期的人胎儿吸收，以帮助神经组织的成熟。极早产儿是在这种生长之前出生的，通常不会在肠外营养中获得“预先形成的”DHA，或者从母乳银行获得低水平的母乳。此外，早产儿通常需要维持生命的治疗，包括呼吸机支持和高浓度氧气，并面临与高氧性肺损伤相关的炎症风险。支气管肺发育不良(BPD)是最常见的早产儿疾病之一，与母婴炎症反应密切相关。被诊断为BPD的婴儿肺泡形成减少，经常需要较长时间的呼吸支持。此外，患有BPD的婴儿通常表现出神经发育延迟，并面临其他医疗问题的风险，这些问题进一步损害了他们的整体健康。中心假说是DHA通过改变RAGE的表达和信号通路，减少白细胞的趋化，从而减轻高氧所致的肺损伤。目的1将验证补充DHA通过调节可溶性RAGE(SRAGE)水平和活性来减轻炎症的假设。SRAGE是由膜结合的RAGE胞外区(MRAGE)的蛋白水解性裂解而产生的。SRAGE可增强单核细胞的趋化性，促进单核细胞成熟分化。这一目标将研究在高氧环境下DHA降低sRAGE水平的机制。目的2将验证补充DHA改变RAGE介导的信号通路的假设。DHA可以通过直接与配体结构域结合或影响配体结合或激活受体的能力来传播或拮抗受体介导的信号转导。这一目标将研究DHA减少细胞内促炎信号的机制。目的3将验证这一假说，即哺乳妇女补充DHA将为早产儿提供DHA，并导致母亲和婴儿的SRAGE表达和炎症反应减少。这些研究将在早产的情况下调查DHA对sRAGE水平的影响。这项建议中概述的研究将结合已建立的高氧暴露和肺发育受阻的新生小鼠模型与早产儿的临床研究相结合，以探讨DHA减少炎症和促进肺生长的机制。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A dietary approach to increase in-stent stenosis and face validity of a rat model for arterial angioplasty and stenting.

一种增加支架内狭窄的饮食方法，并提高动脉血管成形术和支架置入术大鼠模型的有效性。

DOI：
10.1016/j.atherosclerosis.2011.09.021
发表时间：
2011
期刊：
Atherosclerosis
影响因子：
5.3
作者：
Kleinedler,JamesJ;Orchard,ElysseA;Foley,JohnD;Rogers,LynetteK;Hebert,ValeriaY;Dugas,TammyR
通讯作者：
Dugas,TammyR

Docosahexaenoic Acid and Amino Acid Contents in Pasteurized Donor Milk are Low for Preterm Infants.

对于早产儿来说，巴氏灭菌供乳中的二十二碳六烯酸和氨基酸含量较低。

DOI：
10.1016/j.jpeds.2010.06.017
发表时间：
2010
期刊：
The Journal of pediatrics
影响因子：
0
作者：
Valentine,ChristinaJ;Morrow,Georgia;Fernandez,Soledad;Gulati,Parul;Bartholomew,Dennis;Long,Don;Welty,StephenE;Morrow,ArdytheL;Rogers,LynetteK
通讯作者：
Rogers,LynetteK

Stress adaptation and the resilience of youth: fact or fiction?

青少年的压力适应和恢复能力：事实还是虚构？