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 #
2R01NS064404-05
Application #
8722168
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Owens, David F
Project Start
2009-02-15
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$404,936
Indirect Cost
$157,464
Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Sellers, Drew L; Bergen, Jamie M; Johnson, Russell N et al. (2016) Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration. Proc Natl Acad Sci U S A 113:2514-9
Cheng, Yilong; Wei, Hua; Tan, James-Kevin Y et al. (2016) Nano-Sized Sunflower Polycations As Effective Gene Transfer Vehicles. Small 12:2750-8
Tan, James-Kevin Y; Sellers, Drew L; Pham, Binhan et al. (2016) Non-Viral Nucleic Acid Delivery Strategies to the Central Nervous System. Front Mol Neurosci 9:108
Tan, James-Kevin Y; Pham, Binhan; Zong, Yujin et al. (2016) Microbubbles and ultrasound increase intraventricular polyplex gene transfer to the brain. J Control Release 231:86-93
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
Choi, Jennifer L; Tan, James-Kevin Y; Sellers, Drew L et al. (2015) Guanidinylated block copolymers for gene transfer: A comparison with amine-based materials for in vitro and in vivo gene transfer efficiency. Biomaterials 54:87-96
Wang, Christine E; Stayton, Patrick S; Pun, Suzie H et al. (2015) Polymer nanostructures synthesized by controlled living polymerization for tumor-targeted drug delivery. J Control Release 219:345-54
Tan, James-Kevin Y; Choi, Jennifer L; Wei, Hua et al. (2015) Reducible, Dibromomaleimide-linked Polymers for Gene Delivery. Biomater Sci 3:112-120
Chu, D S; Sellers, D L; Bocek, M J et al. (2015) MMP9-sensitive polymers mediate environmentally-responsive bivalirudin release and thrombin inhibition. Biomater Sci 3:41-5
Tan, James-Kevin Y; Choi, Jennifer L; Wei, Hua et al. (2015) Reducible, dibromomaleimide-linked polymers for gene delivery. Biomater Sci 3:112-20

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