On-Going Projects
Study of Iron regulated BBB function in Alzheimer's disease using brain-on-chip
Using a state-of-the-art organ-on-chip technology we aim to better understand the molecular pathways involved in the regulation of BBB function.
We have found that the protein HIF2α protects BBB function and therefore aim to elucidate how HIF2α regulates and protects BBB integrity, potentially using either HIF2α itself or an associated protein as a possible treatment target against the BBB disruption found in the initial stages of Alzheimer’s disease (AD).
We will use our brain-on-chip as a basis for an in vitro AD model and an AD mouse model to ascertain HIF2α’s protective abilities and therapeutic potential.
Ultimately, our goal is to discover therapeutic targets from the HIF2α pathway that can be manipulated with the use of specific pharmacological compounds or adopt clinically approved HIF2α stabilizers and repurpose the drug for AD treatment.
Brain-on-chip A. 3D image acquired of the brain-on-chip model with immunostaining for the nucleus (blue), Ve-cadherin (red) and HIF2α (Cyan). B. A permeability assay to measure BBB functionality, Sodium fluorescein (NaF) (Green) is injected in a flow system into the luminal chamber and the amount of NaF that leaks through to the abluminal side is measured and quantified.
Diabetes, Alzheimer's Disease and the BBB
This study led by former Postdoc Fellow Dr. Shirin Elhaik and Msc student Meir Liberman, explores mechanisms that may underlie cognitive impairment in type 2 diabetes (T2D). We hypothesized that T2D can cause blood-brain barrier (BBB) disruption and changes in the insulin signaling pathway at the neurovascular unit (NVU), which might contribute to the process of cognitive decline, indicated by Alzheimer’s disease (AD)-related behavior and neuropathology. We are applying an innovative MRI technology for detecting BBB disruption in four animal groups. At the age of 4, 8 and 12 months animals are scanned for BBB disruption with MRI. At 12 months, we perform memory and behavioral tests. Postmortem immunohistochemical staining of the insulin receptor (IR) and insulin like growth factor 1 receptor (IGF-1R) at three major cell types lining the NVU are planned. This project was funded by the Alzheimer's Association.
BBB Opening Using Electrical Fields to Treat Brain Diseases
This study led by Dr. Shirley Sharabi and PhD student Yael Bresler, explores the usage of low pulsed electrical fields (L-PEFs) for BBB opening to enable sufficient drug delivery to the brain.
Despite aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme (GBM) patients, in part due to poor penetration of therapeutic agents across the blood- brain barrier (BBB), significant tumor infiltration into surrounding tissues and highly resistance to therapeutic apoptotic stimuli.
The current research is designed to study the mechanism and kinetics of BBB opening using L-PEFs, as well as the efficacy of treating various brain diseases including cancer and Alzheimer’s disease.
This kind of treatment is noninvasive and we hope that better understanding of the process will enable creation of treatment protocols for brain diseases.
This project is funded by the Israeli Science Foundation (ISF) and the Israel Cancer Research Fund (ICRF).
L-PEFs study design to enable efficient and safe drug delivery to the brain. Created with BioRender
Protein Engineering- Designing New Chemo-therapies
Collaborating with Prof. Shechter from the Weizmann Institute of Science, we develop new protein-based chemotherapies to better treat cancer.
Blood-Brain Barrier Function in TiO2 Nano-Particles-Induced Neurological deficits: Basic and Clinical Study
Titanium dioxide (TiO2) is one of the most frequently used biomaterials in industry in general and in medicine in particular. The high chemical inertness, physical stability and commercial availability make it a biomaterial of choice in the implant industry, including orthopedic and orthodontic implants as well as stents. Our overall study goal in this project, funded by MOST, is to assess possible cytotoxic effects of increased serum and CSF Titanium levels on the BBB and brain tissues in vitro and clinically. This study is a collaboration between TAU (Gidi Fleminger), Wolfson hospital (Yair Lampl) and The Sheba Medical Center (Cooper, Mardor, Shelly).
