OLFRs in vascular macrophages: a new connection between microbial metabolites and atherosclerosis progression

Project: Research project

Project Details

Description

Gut bacteria, are closely related to several human biological processes and are known that microbial-metabolic pathways have been implicated in atherosclerosis progression. However, the mechanism how microbial metabolites affect atherosclerosis is largely unknown. Macrophages are key cells in disease processes associated with chronic inflammation including atherosclerosis. Very recently, olfactory receptors (Olfr) function has been linked to likely new roles such as the detection of microbial-derived metabolites. My preliminary data shows for the first time the expression of different Olfr in vascular macrophages isolated from atherosclerotic mouse aortas. Olfr can respond to odorants and metabolites that may be produced by micobiota in the intestinal tract. Moreover, they have been found to induce the expression of inflammatory genes. Based on these evidence, I hypothesize that OLFRs expressed in vascular macrophages may sense microbiome-derived metabolites present in the blood and enhance inflammatory responses. To test this hypothesis, I propose three specific aims: Aim 1 is to identify the role played by Olfrs expressed in vascular macrophages analyzing their diet-related expression. Aim 2 is to screen if specific Olfrs are able to detect known microbiome-derived metabolites, dissecting their physiological function. Aim 3 is to test if their interaction influences the atherosclerosis development in western diet conditions using different KO models. To do so the identify Olfr with their known ligands will be tested ex vivo in the whole aorta from ApoE-/- mice kept in different diet condition. Their physiological role will be dissected using qRT-PCR and RNA-seq analysis. Similar experiments will be done for known microbiome-derived metabolites. Finally, specific Olfr knockout mouse and available RTP1/2 double KO mouse into the Apoe-/- background will be applied to measure the atherosclerosis burden in the presence or absence of the Olfrs. The project objectives are to a) identify the Olfrs newly found expressed in several vascular macrophages dissecting their physiological role. b) Identify the interaction mechanism of microbial metabolism products and vascular macrophages. c) Identify if the interactions between vascular macrophages and microbial metabolism products mediated by Olfr is implicated in the initiation and progression of atherosclerosis. d) Propose Olfrs as new therapeutic targets. (AHA Program: Postdoctoral Fellowship)

StatusFinished
Effective start/end date7/1/186/30/20

Funding

  • American Heart Association: $104,000.00

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