Modulating Blood-Brain Barrier Permeability by TRPV4 activation

Summary The long-term vision of this proposed research is to build the next generation of methods to put medicine into the brain and solve the most challenging and impactful neurological diseases. We plan to achieve this by addressing the blood-brain barrier (BBB), the most significant barrier to delivering medicine to the brain.

Specifically, we aim to achieve cell type-specific control of the BBB by installing magnetic “switches” that would allow therapeutic molecules across this barrier ( MagnetoBBB). This idea is based on two of our recent studies. First, we have found that increasing intracellular calcium levels can change the BBB permeability, defined as the

ability of drugs to cross from the blood to the brain, based on our related studies using lasers and nanoparticles to overcome the BBB. Second, our recent work on Ferritin-iron Redistribution to Ion Channels (FeRIC) has shown the ability to induce calcium signals by producing biochemical signals and is safe in several cell types. In this

proposed work, we aim to establish the feasibility of cell-type specific modulation of the BBB with FeRIC and magnetic field for drug delivery into the brain. To achieve these goals, we propose two specific aims. First, we will investigate and optimize the BBB control using a human brain microvascular endothelial cell line or in vitro.

The in vitro system allows us to optimize and express the FeRIC constructs on the microvascular cell line for magnetic field stimulation. We will characterize the calcium and calcium-induced signals inside these cells. We will further determine the BBB changes by measuring the electrical resistance across a cell monolayer consisting

of these cells and the ability of molecules to cross the monolayer. Second, we will study the ability of MagnetoBBB to control BBB inside a rodent brain or in vivo. We will first deliver the FeRIC genes into the microvascular endothelial cells using viral and nonviral methods. We will then investigate the magnetic field

strength and duration needed to change BBB permeability in live brains. Our proposed approach will offer several significant advantages over existing technologies. First, MagnetoBBB offers a physiologically-like mechanism to modulate endothelial calcium levels and BBB permeability. Second, it allows non-invasive and cell-type specific

modulation of BBB with tissue penetrating RF field. Third, MagnetoBBB uses broadly accessible technology suitable for multiple drug dosages such as chemotherapy, as the inexpensive RF coil can be made portable and easily accessible. Lastly, the magnetic BBB switch is compatible with various imaging methods such as MRI

imaging to monitor the BBB opening and brain function. This proposed exploratory R21 addresses the key aspects for a longer-term effort in cell type-specific control of the BBB for brain therapeutics.