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Grant Abstract

Grant Number: 5R01AT006880-02
PI Name: Rogers
Project Title: DHA attenuates Inflammatory Responses Through Altering RAGE Signaling

Abstract: 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.

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