Extracellular Vesicles miRNAs as Mediators of Sleep Fragmentation Effects on Diabetes and Liver Disease Progression
Abstract
This proposal addresses the Fiscal Year 2018 Peer Reviewed Medical Research Program topic areas of sleep and diabetes. The health impact of disturbed and deficient sleep is significant as more than half of all people in the United States report difficulties with sleep or insufficient sleep at various times, while about 50 to 70 million report having chronic sleep problems. It can arise from causes including poor sleep schedules, sleep apnea, post-traumatic stress, and shift work. Also, with aging, both sleep disturbances and metabolic performance are declining. The proposal is highly relevant for military/Veterans, as sleep fragmentation is a known consequence of post-traumatic stress disorder (PTSD) and it increases with aging. Also, with aging and weight gain resultant from transitioning to a less active lifestyle -- pertinent for Veteran population -- the risk for type 2 diabetes and other obesity comorbidities increases steeply. The association between sleep disturbances and increased risk to develop metabolic diseases such as obesity, type 2 diabetes, and liver disease was established by several epidemiologic studies in humans. However, the mechanistic link between the two conditions is poorly understood. In this proposal, we will focus on extracellular vesicles (EVs) that circulate in blood as a potential link between sleep fragmentation and diabetes. These EVs are well established, naturally occurring, and are produced in large enough numbers to constitute a major means of cell-cell communication. They are small entities surrounded by a membrane that contain a diverse assortment of proteins and nucleic acids. EVs represent a particularly intriguing concept in the context of molecular communication between brain and periphery as they can cross the blood-brain barrier and therefore can mediate exchange of proteins and nucleic acids that are otherwise restricted by such barrier. Our novel hypothesis proposes that sleep fragmentation results in changes in the molecular cargo of EVs. We are particularly interested in the composition and role of microRNAs (miRNA), small nucleic acids that have a key role in regulation of gene expression. We propose that during the normal sleep/wake cycle, EVs that are produced by brain cells and other cells contain miRNA that have beneficial metabolic roles and contribute to function of pancreas, liver, and adipose tissue. During sleep fragmentation, the composition in miRNA contained in these EVs changes and the ?protective? miRNAs are depleted. Our focus will be on a particular miRNA species, miR132, that was shown to be critical in neuronal function and to have anti-inflammatory, anti-fibrotic effects. In diseases such as type 2 diabetes, the function of pancreas, liver, and adipose tissue is progressively declining. We propose that sleep fragmentation accelerates this decline in part due to production of these EVs with altered miRNA composition. We will test our hypothesis using proof-of-concept experiments in mice with type 2 diabetes and liver disease and in healthy controls that will be subjected to imposed sleep fragmentation. These models closely resemble human pathology and therefore bear significant potential to translate the findings to human disease. The project is founded on innovative science to uncover the mechanism by which sleep fragmentation influences diabetes progression. We also feel that understanding this mechanism by which sleep influences metabolic performance provides for an opportunity to target a naturally occurring cell-cell communication particle for development of novel diabetes diagnostics and therapies. Completion of our proposed studies will advance the knowledge at a mechanistic level for the role of sleep in diabetes progression. We would classify our proposal as establishing a causal relationship and providing targets for future therapeutic interventions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910053XX0
Entities
People
- Anca Dobrian
Organizations
- Eastern Virginia Medical School
- United States Army