In addition to secreting soluble mediators, colonic epithelial cells also secrete exosomes (a type of nanovesicle) that contain epigenetic material (proteins, transcription factors, RNAs, miRNAs and DNA fragments). Exosomes are thought to be released basolaterally into the mucosa, where they may regulate local innate responses, and apically, where they may functionally modulate cells at a distance along the gastrointestinal tract and regulate the homeostasis of gut microbiota. In the proposed work, we will exclusively focus on the apical secretion of exosomes into the lumen. Our preliminary results demonstrate that exosomes secreted into the lumen by colonic epithelial cells transit along the gastrointestinal tract and are present in feces. Importantly, colonic and fecal exosomes are similar in their sizes (~140 nm) and miRNA compositions, suggesting that exosomes protect the loaded epigenetic material from highly destructive elements, such as the catabolic enzymes found in the gastrointestinal lumen. Our central hypothesis is that fecal exosomes could yield new miRNA biomarker signatures that may be used to diagnose the degree of colitis and as a drug delivery system to reduce colitis.
Our first aim will be to examine the effects of colitis on fecal exosomes, with the aim of identifying new miRNAs that may be used as an intestinal biomarker signature that reflects disease severity.
In Aim 2, we will examine whether the microbiota composition can be modulated by the administration of various miRNA panels.
In Aim 3, we will examine whether orally administered autologous-healthy fecal exosomes, either alone or as a drug carrier, can reduce intestinal inflammation. It is envisaged that the proposed experiments will facilitate the identification of new biomarkers signatures for intestinal inflammation and allow the development of new therapeutic strategies.
We propose to make a longitudinal assessment of biomarkers (miRNAs) that are obtained in a non-invasive manner at various stages of colitis progression. A similar longitudinal study in humans would help pave the way toward personalized medicine in which the analysis of patient-to-patient differences in molecular signatures could allow clinicians to assess the disease status and personalize drug management. The proposed experiments will combine nanotechnology, innate immunity, and microbiotic approaches to develop a novel approach for treating IBD, overall, our proposal is highly innovative, and our ultimate goal is to contribute meaningful news findings and directly improve the diagnosis, management and treatment of intestinal inflammation.
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