Traumatic brain injury (TBI), commonly caused by motor vehicle injury and falls in the young and elderly, afflicts nearly 1.7 million people in the United States each year. n addition to being a leading cause of death in children and young adults, TBI is also a major cause of permanent disability in the United States. There are currently no curative treatments for TBI, and the main course of action is to minimize secondary damage that results from changes in blood pressure, brain swelling, or intracranial pressure that is triggered by the initia injury. The overall goal of this project is to first develop a well-tolerated means of transferring genes to neural progenitor cells in the brain and then to use this technology to direct cortical neurogenesis after injury. We propose to use focused ultrasound to enhance non-viral gene transfer to neural progenitor cells in the brain mediated by a targeted polymer delivery vector, thus enabling the delivery of genes encoding fibroblast growth factor-2 and neurogenin2, proteins shown to enhance neurogenesis and direct neuron differentiation, respectively. We will evaluate in an animal model of TBI whether induced migration and increased neuronal integration can lead to functional improvement through a combination of histology, cognitive evaluations, and motor assessments. .

Public Health Relevance

Despite the enormous physical, emotional and financial toll resulting from the over 1.7 million cases of traumatic brain injury that occur in the United States per year, there is currently no cure available for either the primary or secondary damage that result from these insults. The main goal of this application is to develop a clinically-translatable approach to enhance neurogenesis in the brain. We expect that the technology developed from the proposed work will present a significant advance toward repair of lost neurons in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064404-06
Application #
8823830
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lavaute, Timothy M
Project Start
2009-02-15
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Washington
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Olden, Brynn R; Cheng, Yilong; Yu, Jonathan L et al. (2018) Cationic polymers for non-viral gene delivery to human T cells. J Control Release 282:140-147
Feldmann, Daniel P; Cheng, Yilong; Kandil, Rima et al. (2018) In vitro and in vivo delivery of siRNA via VIPER polymer system to lung cells. J Control Release 276:50-58
Rosenberg, Alexander B; Roco, Charles M; Muscat, Richard A et al. (2018) Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding. Science 360:176-182
Peeler, David J; Thai, Salina N; Cheng, Yilong et al. (2018) pH-sensitive polymer micelles provide selective and potentiated lytic capacity to venom peptides for effective intracellular delivery. Biomaterials 192:235-244
Yen, Albert; Cheng, Yilong; Sylvestre, Meilyn et al. (2018) Serum Nuclease Susceptibility of mRNA Cargo in Condensed Polyplexes. Mol Pharm 15:2268-2276
Lee, Daniel C; Lamm, Robert J; Prossnitz, Alex N et al. (2018) Dual Polymerizations: Untapped Potential for Biomaterials. Adv Healthc Mater :e1800861
Comedy, Yolanda L; Gilbert, Juan E; Pun, Suzie H (2017) INVENTION IS NOT AN OPTION. Technol Innov 18:267-274
Cheng, Yilong; Sellers, Drew L; Tan, James-Kevin Y et al. (2017) Development of switchable polymers to address the dilemma of stability and cargo release in polycationic nucleic acid carriers. Biomaterials 127:89-96
Cheng, Yilong; Wei, Hua; Tan, James-Kevin Y et al. (2016) Nano-Sized Sunflower Polycations As Effective Gene Transfer Vehicles. Small 12:2750-8
Cheng, Yilong; Yumul, Roma C; Pun, Suzie H (2016) Virus-Inspired Polymer for Efficient In?Vitro and In?Vivo Gene Delivery. Angew Chem Int Ed Engl 55:12013-7

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