An in vitro model to study the impact of systemic inflammation on the blood-brain barrier in neurodegenerative disease - This project will utilize an in vitro model of the human blood-brain barrier (hBBB) to study how systemic inflammation following surgery can lead to neuroinflammation and delirium, particularly in cases where patients have BBB damage from a neurodegenerative disease such as Alzheimer's Disease (AD). Post-operative delirium (POD) is a common complication in older adults and can lead to permanent cognitive impairment. As patients with pre-existing dementia are particularly vulnerable to brain injury from delirium, delirium superimposed on dementia or DSD is given special consideration in this project. Currently there is a lack of treatments for DSD because the mechanism is unknown. To help ourselves and others study the mechanism of DSD, we will adapt and advance an in vitro “tissue-on-a-chip” system called the µSiM-hBBB which uses cells derived from human induced pluripotent stem cells to create patient-specific models of the blood-brain barrier (BBB). We have previously demonstrated that this system can mimic the barrier function of the human BBB including its response to acute inflammation. The central hypothesis of this project is that pericyte support is key to the maintenance of a healthy BBB and that loss of pericytes, a characteristic seen in neurodegenerative diseases, increases neuroinflammation in response to systemic inflammation. The first Aim will apply the µSiM-hBBB with novel engineered membranes to identify the mechanism by which pericytes loss leads to weaking of barrier properties in DSD. The second aim will be to use cells from a syngenic iPSC lines that are ApoE3 homozygous or ApoE4 homozygous to study the role of ApoE isoform in creating a ‘diseased’ BBB and whether ApoE3 pericytes can restore barrier function. The final aim will advance the µSiM-hBBB to include an additional compartment with microglia, the resident immune cells of the brain. The activation of microglia will serve as a direct measure of neuroinflammation in the model. Successful completion of the project will clarify how pericytes provide support to the BBB and how their absence may underlie vulnerabilities to brain injury following systemic inflammation. By advancing our tri-culture, patient-specific platform to include ‘disease’ models, we will create a valuable new tool for the field to study the mechanisms of neuroinflammation following surgery, and a platform to discovery new therapies to prevent brain injury in the most vulnerable populations. This work will be completed at the University of Rochester, a tier 1 private research university which facilitates high-level research in a highly collaborative environment. The project will be supported by a team of collaborators and advisors who are experts in various aspects of the proposed project. The PI of the project will take additional courses for training and work with her sponsor and mentors for career development. The training plan will prepare for a career as an independent researcher, including attending conferences, publications, international and industry collaborations, and leading a journal club.
