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THE DEVELOPMENT OF A MULTICELLULAR THREE-DIMENSIONAL NEUROVASCULAR UNIT MODEL FOR STUDYING BLOOD-BRAIN BARRIER INTEGRITY IN DISEASE PATHOLOGIES

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abstract
The lack of in vitro human brain equivalent models with functional neurons and other supporting cell types of the human cortex (astrocytes, microglia, oligodendrocytes, neurons, pericytes, and microvascular endothelial cells) impedes scientific understanding of neurologic disease progression and has significantly limited drug development. These cell types interact in concert, termed the neurovascular units (NVU), and the interactions result in the formation of a blood brain barrier (BBB) which is one of the primary barriers for CNS targeting investigational drugs. Understanding these interactions is essential to the development of drugs to treat a wide array of diseases and neurological disorders. The current two- and three-dimensional in vitro models, in addition to in vivo models, have provided insight on BBB properties. However, these models often fail to mimic the human physiological properties of the NVU because most contain cells of varying species that do not mimic human brain physiology, and often contain artificial components not representative of the environment within the human cortex. Through the use of a spheroid culture system, we seek to develop reproducible three-dimensional in vitro human brain organ equivalent model consisting of all six-major human brain cell types that mimic the normal functions of the human NVU. Our data show the presence of an intact and functional BBB. Furthermore, our results show that the model cannot only be applied in drug toxicity screening but also in neurological disease modeling as well. Our model will overcome some of the limitations of current 2D in vitro models and may have applications in drug discovery and neurotoxicity testing and open the door to individualized patient-specific disease models when used in conjunction with representative cell types derived from induced pluripotent stem cells (iPSCs).
subject
3D Brain Model
Blood-Brain Barrier
Brain Organoid
Drug Discovery
Neurodegenerative Diseases
Neurovascular Unit
contributor
Nzou, Goodwell (author)
Atala, Anthony J (committee chair)
Milligan, Carolanne E (committee member)
Tatter, Stephen B (committee member)
Jackson, John D (committee member)
Lee, Sang J (committee member)
date
2019-05-24T08:35:43Z (accessioned)
2019 (issued)
degree
Molecular Medicine and Translational Science (discipline)
2020-05-23 (liftdate)
embargo
2020-05-23 (terms)
identifier
http://hdl.handle.net/10339/93949 (uri)
language
en (iso)
publisher
Wake Forest University
title
THE DEVELOPMENT OF A MULTICELLULAR THREE-DIMENSIONAL NEUROVASCULAR UNIT MODEL FOR STUDYING BLOOD-BRAIN BARRIER INTEGRITY IN DISEASE PATHOLOGIES
type
Dissertation

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