Our long-term goal is to induce a regulatory T cell (Treg) response following traumatic brain injury TBI and enhance the neuroprotective effects with cell-directed vascular endothelial growth factor (VEGF)- nanoformulations. We hypothesize that T cell targeted delivery of VEGF-nanoformulations will provide synergistic protection to both the injured vasculature and parenchyma. TBI initiates a complicated biochemical cascade that includes a strong neuroinflammatory component. Treg can infiltrate the brain in response to injury and control the inflammatory response. Granulocyte macrophage colony stimulating factor (GM-CSF), can induce a potent Treg response and provide neuroprotection. To augment this neuroprotective response, we propose loading these cells with VEGF to stimulate regeneration of neurons and endothelium. VEGF induces angiogenesis and neurogenesis and can reduce morbidities after experimental brain injury. However, systemic administration of VEGF is problematic and requires targeted delivery. We propose a two-step experimental approach. First, we will induce a neuroprotective T cell response and second use that induction to carry VEGF to the brain. We propose 3 specific aims utilizing a combination of in vitro and in vivo trauma models with supporting biochemical, neuroimaging, behavioral and targeted drug delivery methods.
In Specific Aim 1, we will produce VEGF-nanoformulations with anionic block copolymers and will test these complexes for biological effect in vitro and in vivo.
In Specific Aim 2, we will characterize the effect of GM-CSF following trauma. Neuroprotective outcomes will be evaluated by immunohistochemical detection of glia and neuronal markers, morphologic determination of the lesion size, and behavioral tests.
In Specific Aim 3, we will determine the rate of in vitro uptake and release of the VEGF nanoformulations in Treg. In this aim, we will utilize bioimaging, behavior, and histology to determine , outcomes following treatment with T cell directed VEGF-nanoformulations. This research is an essential first step to developing and delivering novel nanotherapeutics for the treatment of clinical TBI.

Public Health Relevance

Traumatic brain injury (TBI) causes neuronal cell death, cerebrovascular damage, and inflammation. Regulatory T cells infiltrate areas of damage to control inflammation and may also be used to deliver nanoformulated vascular endothelial growth factor to induce regeneration of damaged tissue. We will test this strategy using in vitro and in vivo trauma models with biochemical, neuroimaging, and behavioral methods. This strategy could provide a synergistic combination therapy for TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103480-07
Application #
8730198
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Soni, Kruti S; Lei, Fan; Desale, Swapnil S et al. (2017) Tuning polypeptide-based micellar carrier for efficient combination therapy of ErbB2-positive breast cancer. J Control Release 264:276-287
Karuturi, Bala V K; Tallapaka, Shailendra B; Yeapuri, Pravin et al. (2017) Encapsulation of an EP67-Conjugated CTL Peptide Vaccine in Nanoscale Biodegradable Particles Increases the Efficacy of Respiratory Immunization and Affects the Magnitude and Memory Subsets of Vaccine-Generated Mucosal and Systemic CD8+ T Cells in a Diamet Mol Pharm 14:1469-1481
Fan, Wei; Zhang, Wenting; Jia, Yinnong et al. (2017) Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers. Mol Pharm 14:1405-1417
Chen, Shixuan; Ge, Liangpeng; Mueller, Aubrey et al. (2017) Twisting electrospun nanofiber fine strips into functional sutures for sustained co-delivery of gentamicin and silver. Nanomedicine 13:1435-1445
Chen, Shixuan; Ge, Liangpeng; Gombart, Adrian F et al. (2017) Nanofiber-based sutures induce endogenous antimicrobial peptide. Nanomedicine (Lond) 12:2597-2609
Jiang, Jiang; Chen, Shixuan; Wang, Hongjun et al. (2017) CO2-expanded nanofiber scaffolds maintain activity of encapsulated bioactive materials and promote cellular infiltration and positive host response. Acta Biomater :
Shrishrimal, Shashank; Kosmacek, Elizabeth A; Chatterjee, Arpita et al. (2017) The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues. Antioxidants (Basel) 6:
Souchek, Joshua J; Davis, Amanda L; Hill, Tanner K et al. (2017) Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. Mol Cancer Ther 16:1819-1830
Smolsky, Joseph; Kaur, Sukhwinder; Hayashi, Chihiro et al. (2017) Surface-Enhanced Raman Scattering-Based Immunoassay Technologies for Detection of Disease Biomarkers. Biosensors (Basel) 7:
Lakshmanan, Imayavaramban; Salfity, Shereen; Seshacharyulu, Parthasarathy et al. (2017) MUC16 Regulates TSPYL5 for Lung Cancer Cell Growth and Chemoresistance by Suppressing p53. Clin Cancer Res 23:3906-3917

Showing the most recent 10 out of 74 publications