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Engineered Serum Markers for Noninvasive Monitoring of Gene Expression in the Brain

Sangsin Lee, Shirin Nouraein, James J. Kwon, Zhimin Huang, View ORCID ProfileJerzy O. Szablowski
doi: https://doi.org/10.1101/2022.07.17.500352
Sangsin Lee
1Department of Bioengineering, Rice University, Houston, TX 77030, USA
2Rice Neuroengineering Initiative, Rice University, Houston, TX 77030, USA
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Shirin Nouraein
1Department of Bioengineering, Rice University, Houston, TX 77030, USA
2Rice Neuroengineering Initiative, Rice University, Houston, TX 77030, USA
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James J. Kwon
1Department of Bioengineering, Rice University, Houston, TX 77030, USA
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Zhimin Huang
1Department of Bioengineering, Rice University, Houston, TX 77030, USA
2Rice Neuroengineering Initiative, Rice University, Houston, TX 77030, USA
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Jerzy O. Szablowski
1Department of Bioengineering, Rice University, Houston, TX 77030, USA
2Rice Neuroengineering Initiative, Rice University, Houston, TX 77030, USA
3Synthetic, Systems, and Physical Biology Program, Rice University, Houston, TX 77005, USA
4Applied Physics Program, Rice University, Houston, TX 77005, USA
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  • ORCID record for Jerzy O. Szablowski
  • For correspondence: jszab@rice.edu
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ABSTRACT

Noninvasive efforts to map brain gene expression have been hampered by low sensitivity and limited access to the brain. Here, we introduce a new platform that enables multiplexed, noninvasive, and site-specific monitoring of brain gene expression through a novel class of engineered reporters called Released Markers of Activity (RMAs). Instead of detecting gene expression in the less accessible brain, RMA reporters exit from a known brain region into the blood, where they can be easily measured with biochemical techniques. Expressing RMAs at a single brain site, typically covering ∼1% of the brain volume, provides up to a 39,000-fold signal increase over the baseline in vivo. Further, expression of RMAs in as few as several hundred neurons was sufficient for their reliable detection. When placed under a promoter upregulated by neuronal activity, RMAs could be used to measure neuronal activity in specific brain regions with a simple blood draw. We found that chemogenetic activation of cells expressing Fos-responsive RMA increased serum levels of RMA over 4-fold compared to non-activated controls. By contrast, a control RMA expressed under a constitutive neuronal promoter did not show such upregulation, demonstrating multiplexed ratiometric measurement with RMAs and proving specificity of neuronal activity discrimination. Together, our study pioneers a new noninvasive paradigm for repeatable and multiplexed monitoring of gene expression in an intact brain with sensitivity that is currently unavailable through other noninvasive gene expression reporter systems.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 18, 2022.
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Engineered Serum Markers for Noninvasive Monitoring of Gene Expression in the Brain
Sangsin Lee, Shirin Nouraein, James J. Kwon, Zhimin Huang, Jerzy O. Szablowski
bioRxiv 2022.07.17.500352; doi: https://doi.org/10.1101/2022.07.17.500352
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Engineered Serum Markers for Noninvasive Monitoring of Gene Expression in the Brain
Sangsin Lee, Shirin Nouraein, James J. Kwon, Zhimin Huang, Jerzy O. Szablowski
bioRxiv 2022.07.17.500352; doi: https://doi.org/10.1101/2022.07.17.500352

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