Recent advances in cell biology have reported a role for extracellular vesicles (EVs) in cell-cell signaling. These are small 'packets' of cellular contnt (such as RNA) that can be shed from cells, and reflect the characteristics of the originating cells Studies in cancer have shown these EVs to be useful markers of neoplastic cells, and are a mechanism to clear cancer drugs and influence surrounding cells. Although their use as a signature of abnormal cell types is clinically interesting, the ability of EVs to influence the actvity of neighboring cells is of great potential significance in our understanding of disease processes. In inflammatory conditions, EVs released from local cells could have immune modulating, and drug clearance, properties. In patients with Inflammatory Bowel Disease (IBD), the underlying chronic intestinal inflammation exhibits variations in both location and severity over time. Contemporary means of monitoring disease activity are limited by costs, complications or specificity (e.g. CT, colonoscopy). Preliminary work from the applicant's K23-funded project has isolated EVs from the intestinal lumen of patients with active colitis. These cellular signaling vehicles preserve their RNA and protein content from degradation, making them suitable for detection in fecal samples. This application proposes to obtain intestinal fluid, fecal and tissue samples from patients with IBD, and healthy controls, to test them for the presence of EVs, and describe their characteristics based on content and surface markers. The study will compare levels, and content of, EVs isolated from the intestinal tract between patients with active and inactive disease as a disease activity comparator. It will also determine whether fecal samples reflect the content of EVs that are isolated from the intestinal lumen. In addition, this study wil measure the effect of these isolated EVs on intestinal epithelial cells in culture, to determine if they alter the gene expression patterns and chemotactic properties of these cells. This proposal would generate preliminary data to support further examining the role of luminal EVs as markers of disease activity, and mediators or inflammatory signals throughout the intestinal tract. The impact of secreted EVs on the composition and function of the intestinal microbiome is also planned in future studies.

Public Health Relevance

Inflammatory Bowel Disease affects nearly 2 million Americans. This proposal will describe cellular signals released into the intestinal tract that could be used to measure disease activity in a safe and efficient manner.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK105161-01
Application #
8870956
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
2015-04-01
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Vaughn, Byron P; Vatanen, Tommi; Allegretti, Jessica R et al. (2016) Increased Intestinal Microbial Diversity Following Fecal Microbiota Transplant for Active Crohn's Disease. Inflamm Bowel Dis 22:2182-90
Mitsuhashi, Shuji; Feldbr├╝gge, Linda; Csizmadia, Eva et al. (2016) Luminal Extracellular Vesicles (EVs) in Inflammatory Bowel Disease (IBD) Exhibit Proinflammatory Effects on Epithelial Cells and Macrophages. Inflamm Bowel Dis 22:1587-95
Jiang, Z Gordon; Wu, Yan; Csizmadia, Eva et al. (2014) Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma. Purinergic Signal 10:611-8