The brain?s immune system is critical for maintaining brain health and cognitive function. Neuroinflammation is responsible for clearing of pathogens and supporting neuron health. However, when neuroinflammation goes out-of-control they can contribute to permanent or progressive cognitive loss in brain injury, Alzheimer?s disease, and many other neurological conditions. Treatment of these diverse diseases would benefit from better understanding of how to regain control of healthy neuroinflammation. Importantly, healthy neuroinflammation is a dynamic process that requires first a pro- followed by an anti-inflammatory response. However, there has been limited investigation to identify the dynamics of healthy neuroinflammation or to determine how to control brain immune cells to restore healthy function. The focus of this CAREER project is microglia, which are the main immune cells of the brain that dynamically respond to pro- and anti-inflammatory stimuli. Their behavior will be explained using quantitative engineering models similar to those used in the design of autopilots. This novel engineering approach will provide new fundamental knowledge on the dynamics of brain immune cells and the relationship between these dynamics and their function to clear pathogens. Moreover, it will enable design of treatments that will promote healthy brain immune function. The Investigator will integrate these research activities with a strong educational outreach program to teach underprivileged elementary school students about the immune system. Planned activities include developing a summer camp on engineering and biological science that includes reinforcement though generation of materials that can be used through-out the school-year and rigorous assessment of student grades and interest in engineering and science. The Investigator's goal is to open the minds of these students to thinking and working as both engineers and scientists and to foster their interest and aspirations to working in STEM fields.
The Investigator?s long-term career goal is to create and use engineering methods to elucidate mechanisms driving brain immune function and to actively regulate these mechanisms to reduce immune-based injury and promote brain health. Toward this goal, this CAREER project is to develop a novel paradigm to quantitatively understand the immune cell response to exogenous stimuli and to use this understanding to implement a control system for active regulation of microglia (ARM). The project will create ARM controllers that will regulate multiple markers of diverse microglial states that will be applicable both in vivo and in vitro and will identify quantitative models of microglial cell state dynamics in response to multiple pro- and anti-inflammatory inputs. The research plan is organized under three objectives. The FIRST Objective is to use top-down data driven modeling from control systems engineering to quantify the dynamics of microglial activation in response to biochemical stimuli and use these models to design open-loop control strategies for temporally regulating microglial response in vitro. This will be accomplished through employing flow cytometry to quantify microglial marker dynamics using protein markers known to indicate homeostatic, anti-inflammatory and pro-inflammatory states; identifying a data-driven dynamic system model for each marker; using results obtained to determine the appropriate system input in terms of an optimal control function; and then validating the system by determining whether or not temporal regulation of primary murine microglia response will modify uptake of Amyloid beta, a key pathogen in Alzheimer?s Disease. The SECOND Objective is to determine if quantitative models can be used as part of a real-time feedback strategy to reduce error between desired and actual trajectory of microglial activation. This will be accomplished by establishing a microfluidic cell culture platform to enable real-time feedback control of microglial activation markers; enabling real-time monitoring of microglial activation state via microglial transduction with fluorescent reporters for each of the markers studied in the first objective; and then determining, by placing the microfluidic system and transduced reporter microglia in a live-cell imaging system, if the feed-back control ?autopilot? system is capable of regulating a population of microglia to a desired set-point or trajectory. The THIRD Objective is to determine if control systems modeling can be used to model and design open-loop immune trajectories in mice. This will be accomplished by identifying a data-driven model for microglial markers in vivo and combining these dynamic models to predict open-loop input strategies using the same modeling framework as used in the first and second objectives; and then testing if modulation of microglial activity will reduce Amyloid beta pathology in a mouse model of Alzheimer?s disease.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.