Brain swelling is a serious complication of traumatic brain injury (TBI), ischemic stroke and other serious conditions. TBI and stroke afflict 1.4M and 700K persons per year in the US alone. They are a costly health care burden and a devastating social burden. Current treatments for brain swelling are limited and generally ineffective, highlighting the dramatic unmet need for better therapeutics. A better understanding of the molecular pathways and cellular mechanisms is sorely needed to identify new drug targets and predictive biomarkers that can stratify patients for clinical treatment decisions. The goal of this project is to identify new drug targets and biomarkers of response for cytotoxic edema of astrocytes. We will use a novel and innovative technology that we have developed that takes an unbiased approach to functionally identifying the causal mediators of brain cell swelling. Our approach uses a large panel of genetically diverse astrocyte lines to identify the genes and pathways that mechanistically underlie cytotoxic edema. In Phase I, we developed a high throughput kinetic assay for astrocyte swelling that is robust and scalable for screening compounds that induce or block swelling. In Phase II we will screen 300 genetically diverse astrocyte cell lines and then map and identify the genes that mediate response to inducers and blockers of cell swelling. Validation of candidate target genes will be conducted in both human and mouse astrocytes. Human genes that modify human astrocyte response that are also therapeutically accessible target genes for novel drug discovery are the ultimate aims and products of this project.

Public Health Relevance

Brain swelling (cerebral edema) is a serious consequence of many disorders such as traumatic brain injury and stroke. A more complete understanding of the molecular pathways underlying cerebral edema is a critical bottleneck in the development of new drugs for brain swelling. We want to understand the molecular mechanisms underlying swelling in astrocytes, the most abundant cell type in the brain, toward the discovery of more effective treatments for brain edema. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44NS100202-02
Application #
9679250
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fertig, Stephanie
Project Start
2016-09-30
Project End
2020-08-31
Budget Start
2018-09-30
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Predictive Biology
Department
Type
DUNS #
144728818
City
Carlsbad
State
CA
Country
United States
Zip Code
92010