Genetic circuits for targeted modulation of neuroinflammation - Project summary/Abstract
Neuroinflammation plays a critical role in neurodegenerative diseases and cognitive functions. Current methods
to study neuroinflammation in animal models are extremely limited, primarily restricted to endpoint histological
analysis. Furthermore, a means to precisely control the neuroinflammatory response is lacking.
The goal of this proposal is to develop the first family of biosensors that can be used to report and dynamically
regulate changes in inflammation within the brains of live animals. This is accomplished by a synthetic gene
circuit where a sensor of dynamic changes in inflammatory cytokines translates these changes into production
of proteins capable of mitigating pathological inflammation. Building on our experience with bioluminescent
optogenetics tools, we will develop a light emitting Bioluminescent Kinase Sensor (BlinKS) that activates a light
sensing transcription factor driving cytokines to reduce inflammation. Our first aim is to develop and optimize
sensors based on split luciferases that will produce light in the presence of a molecule produced in the
inflammatory signaling cascade. Inflammation dependent light production is then leveraged to activate light
sensitive optogenetic proteins to control cellular activity. Our second aim is to utilize these light emitting sensors
of the inflammatory cascade in a genetic circuit to control the expression of an anti-inflammatory cytokine to
control inflammation as a self-regulating therapeutic in a transgenic mouse model of neuroinflammation. Our end
goal is to apply these inflammation modulators to various animal models where neuroinflammation is a key
pathologic hallmark such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. We expect
these modulators to have high translational potential to combat neurodegeneration and other inflammatory
disorders.
This project is enabled by a multidisciplinary team of five labs with expertise in high throughput screening
methodologies for biosensor engineering, optogenetics, genetic circuits, high throughput single-cell sequencing
and gene expression analysis, neuroinflammation, neurodegeneration and in vivo applications. We anticipate
that these new biosensors and modulators will be transformative tools for both neuroscience and immunology
research and be a powerful therapeutic by enabling noninvasive imaging of inflammatory responses and
selective, inflammation-dependent immunomodulation with cell type specificity that can be used in deep brain
structures, across large areas, in behaving animals.
