Engineering Human Brain Neurovascular Niche for Modeling Brain Diseases

点击翻译按钮获取中文摘要

Neurovascular unit (NVU) regulates efficient blood support and neuron functions in the brain. Its dysfunction or breakdown is associated with a wide variety of neurological disorders including Alzheimer’s disease (AD) and contribute to both initiating and exacerbating neuropathology. The underlying biological mechanisms, however, remain insufficiently understood for the design of effective prevention or treatment. The progress in under- standing these mechanisms has been limited, partially, due to the lack of appropriate and manipulatable pre- clinical models for human brains that can recapitulate the complex cellular, biophysical and biochemical inter- actions in human NVUs. To address these challenges, we have established an interdisciplinary team with ex- pertise in microvascular engineering and vascular biology, and stem cell and neural biology to reconstruct hu- man brain neurovascular niche for the understanding of NVU functions in both normal and diseased conditions. We will exploit our synergistic capabilities to generate NVU through brain organoids technology with perfusable brain microvessels. We will test the hypothesis that the vascular cells and complex neural circuits interact in both time and space, that perfusable brain microvessels provide maturation cues to the neurons, whereas ge- netic background of neurons influences the function of both vascular and neuron functions in the NVU. We will interrogate the molecular and cellular changes of different cell types in vascularized brain organoid and how this may be relevant to a disease state using AD patient derived iPSCs. Once successful, this project will de- velop and exploit new vascular engineering technology, stem cell biology and bioinformatics to develop and understand the structure and function of the neurovascular unit for modeling neurodegenerative diseases, which further advances therapeutic development.