Defining mechanisms of blood-brain barrier dysfunction in cerebral small vessel disease using advanced 3D in vitro models.

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Neurodegenerative disorders (NDDs) are incurable and debilitating conditions that result in the progressive death of brain cells. This leads to movement disorder, cognitive decline and increased disability. Current therapies for NDDs treat symptoms, not the underlying pathological changes. The NDDs are therefore major challenges to healthcare providers and research scientists. NDDs occurs mostly in older people in whom cerebral small vessel disease (cSVD) is common and contributes to at least 45% (~21 million people) of dementia worldwide. The aggregate societal cost of dementia is £26 billion per year, including £8.6 billion for NHS and social care. There is a clear and unmet clinical need to develop new therapies based on understanding the molecular pathologies.The human brain needs a stable microenvironment to ensure proper functioning. A specialized multi-cellular blood vessel structure, the blood-brain barrier (BBB), regulates the flow of molecules between the blood and the brain. A key aspect of NDD development is the leakiness of the BBB and the spread of inflammatory mediators (messengers that acts on blood vessels and/or cells to promote an inflammatory response) around the brain. We do not understand how these mediators cross the tight barrier and cause BBB breakdown, or the precise role of different BBB cells in these processes.NDDs are diverse in their pathophysiology and effective treatments are urgently needed. Many drugs that have been previously shown to be effective in animals have failed to produce the same effects in humans, simply because we are different. Moreover, animal studies do not allow studying disease mechanisms in a model that is free from secondary, age-related complications, while 2D cell-based models are often too simplified to sufficiently recapitulate BBB biology. For this reason, I have designed a simpler, faster, and more physiologically-relevant human cellular model of disease. In this project, I will develop my novel, dynamic, microphysiological 'BBB-on-a-chip' that mimics the relevant physiology and functionality of the human brain. I will determine how factors such as blood pressure, blood flow rate and heartbeat control BBB function. I will use cells harvested directly from human brains (primary cells) and stem cells with cSVD-relevant genetic mutations using a state-of-the-art genetic editing tool called CRISPR-Cas9 to generate a physiologically-relevant human disease model. I will investigate how the biology of brain cells changes when supported by an intact or a leaky BBB. This new analysis of BBB function in a physiological model will lead to the identification of new cellular processes relevant to cSVD progression, and help us understand how to harness the BBB to shield the brain from disease.This is not possible using any other approach. I am therefore poised to develop significant new understanding of brain function in health and disease and discover new drugs and targets that can stop the occurrence and development of related dementias.