High Throughput Discovery of Blood-Brain Barrier Functional Components
In patients with Alzheimer's disease (AD) and dementia, the blood vessels of the brain become leaky, which worsens symptoms like memory loss. We are trying to identify why these blood vessels become leaky. If we understand the cause of this leakage, we can potentially target it with new drugs to improve patient outcomes.
The goal of our project is to better understand how the blood vessels in the brain form the blood-brain barrier (BBB), which normally protects the brain from toxic substances but becomes leaky in diseases like Alzheimer’s and dementia. In the first portion of the project, we are using a cell line that mimics BBB function and systematically removing every human gene to test their effects on barrier properties. The most promising “hits” from this screen are to be re-tested in human BBB cells that we produce in the lab. Finally, we are confirming that these genes are lost in mice whose BBB has been disrupted, thus demonstrating their functional importance.
Our proposal is the first to merge genome editing technology with explorations of BBB function. Furthermore, we are able to generate an unlimited quantity of human BBB using induced pluripotent stem cells (iPSC, a stem cells technology that grows cells from tissue samples from living adults). Together, these techniques will allow us to unravel the mysteries of BBB function to understand why the blood vessels in the brain start to leak and how this contributes to serious brain diseases. Once our study is complete, we will use this information to hunt for new drugs that manipulate these new targets and prevent BBB leakiness. These drugs may provide new treatment options for Alzheimer’s and dementia.
About the Researcher
Dr. Ethan Lippmann graduated from the University of Illinois at Urbana-Champaign with a bachelor’s degree in chemical engineering in 2006. He next trained as a Dahlke/Hougen graduate fellow in the Department of Chemical Engineering at the University of Wisconsin-Madison under the supervision of Dr. Eric Shusta. During this time, he pioneered the use of human iPSCs (hPSCs) for constructing in vitro models of the blood-brain barrier. After defending his thesis in 2012, he transitioned to the Wisconsin Institute for Discovery to conduct research on spinal cord tissue engineering in the laboratory of Dr. Randolph Ashton. As a postdoctoral fellow, he developed novel paradigms for generating neural cells from hPSCs, and during this time he was supported by a fellowship from the Wisconsin Stem Cell and Regenerative Medicine Center and a National Research Service Award from the NIH. In the fall of 2015, Dr. Lippmann joined the Department of Chemical and Biomolecular Engineering at Vanderbilt University to continue his efforts in the fields of neurovascular modeling and therapeutic discovery.
My uncle, father-in-law, and great-uncle (now deceased) all suffer from Parkinson's disease, and I have watched them struggle with their symptoms. My desire to better understand mechanisms of neurological disease and help develop new treatment options is a personal quest, and this particular project would not be possible without the support and generosity of the BrightFocus Foundation and its donors.
First published on: July 11, 2017
Last modified on: April 2, 2020