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Research & Initiatives

The goal of our lab is to understand the timing of communication between the brain and the periphery under physiologic and disease conditions. The blood-brain barrier (BBB) is a tightly-regulated structure that simultaneously protects the brain from harmful environmental insults and allows transport of endogenous molecules. Understanding regulation of the BBB is important for addressing effects of the periphery on the brain and for improving methods of drug delivery. 

Prior research has shown that the humoral factors have different oscillation patterns between the blood and the brain, suggesting that the blood-brain barrier is not only physically restrictive, but also temporally restrictive. Internal time cues come from the circadian clock, a molecular feedback loop present in many tissues, that entrains to the day:night cycle and coordinates molecular, cellular, and behavioral rhythms. Our work has identified the circadian clock in the BBB as having a critical role in the temporal restriction of xenobiotics from the brain in both Drosophila and mammals. Existing studies of peripheral effects on behavior have largely overlooked both timing and the blood-brain barrier.

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We have 4 interrelated research questions:

 

Project 1: What endogenous molecules are regulated by the BBB clock? 

 

A key mission of the lab will be to identify the peripheral molecules that are gated by the circadian clock in the BBB. The BBB is a tightly regulated barrier that allows transport of nutrients, hormones, and metabolic waste products. We and others have found that trafficking of molecules across the BBB is dependent on the time of day. While these approaches gave us a proof of concept of the temporal gating of the brain, it may represent only a fraction of the molecules that are regulated by this gate. The goal of this project is to identify periphery-to-brain processes under BBB circadian clock control.

 

Project 2: Does the intrinsic rhythm in the blood-brain barrier affect behavior and/or neuronal function?

 

Circadian regulation of active efflux in the BBB suggests that the clock is important for transmission of critical signals from the periphery to the brain. We propose to test the idea that the BBB clock controls passage of peripheral molecules to affect behaviors through genetic manipulation of the circadian clock.

 

Project 3: How does the BBB rhythm and inflammation affect each other?

 

This project examines the bi-directional relationship between inflammation and the BBB clock. Peripheral clocks such as the one present in the BBB are more susceptible to inflammation compared to central clocks. We propose to examine the BBB rhythms that are affected by inflammation with the longer-term goal of determining whether loss of barrier rhythms contributes to pathology of inflammatory disorders. 

 

Project 4: How are BBB endothelial rhythms affected by other brain cell types?

 

The rhythm of xenobiotic efflux in the mouse is robust; however, our BBB endothelial cell culture model rhythms are much weaker. Our aim here is to determine the contribution of astrocytes, pericytes, neurons, and other brain cell types to BBB rhythms.