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)
Type
Exploratory Grants (P20)
Project #
5P20GM103480-07
Application #
8730198
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
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
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