Over 1.7 million persons sustain a traumatic brain injury (TBI) in the U.S. alone. Current diagnostic techniques for TBI are excellent in detecting gross morphological alterations (i.e. hemorrhagic events, changes in water content, or the emergence of anisotropic tissue densities), however, they do little to detect the immediate molecular/cellular alterations. Moreover, current treatment modalities for TBI focus on minimizing the secondary symptoms and complications associated with TBI;however, no clinical treatments currently exist to treat the underlying neuropathology for any level of injury severity ranging from mild to severe. Therefore, there is an obvious need to develop diagnostic and therapeutic (theranostic) intervention strategies that recognize and exploit the molecular pathological events. The long-term goal of this project is develop theranostic platform technologies that exploit pathological signatures of neural injury at the molecular level. To achieve this goal, the primary objective of this proposal is to demonstrate the utility of single chain antibody fragments (nanobodies) that recognize and exploit the heterogeneous injury microenvironment as targeting motifs for nanoscale targeted probes. The rationale for the proposed research is that nanobody probes developed to recognize the complexity of the neural injury environment at the molecular level will significantly enhance the sensitivity of future theranostic modalities for TBI. This objective will be realized through the pioneering nanotechnology platform that will be based on unique nanobodies identified with complex phage biopanning assays against molecular targets that are prevalent during various stages of the injury sequelae (e.g. fibrin, reactive astrocytes, degenerative neurons). This platform will then b employed to explore the following approaches to address current limitations in current diagnostic and therapeutic interventions. Approaches: 1. Exploit pathological signatures at the cellular/molecular level to develop targeting contrast agents for dual imaging modalities, 2. Provide localized temporal delivery of multiple therapeutics to address the progression of TBI pathology, and 3. Redecorate injury extracellular landscape to promote and support neural regeneration within the injury penumbra. The proposed research platform is innovative because it exploits the conformational recognition of the epitope/antigen interaction to develop nano-scaled probes with specificity to the complex neural injury environment. This contribution is significant because the technology developed in this proposal has the potential to revolutionize the approach for TBI theranostics.

Public Health Relevance

The proposed research is relevant to public health because the discovery of targeting nanobodies that identify molecular pathologies associated with neural injury will enable the development of more accurate diagnostic modalities and targeted delivery of therapeutic interventions for traumatic brain injury. Therefore, this project is relevant to NIHs mission as it focuses on developing an innovative targeting strategy to improving detection and treatment of traumatic brain injury, the leading cause of injury related death in America.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2HD084067-01
Application #
8757308
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Michel, Mary E
Project Start
2014-09-15
Project End
2019-08-31
Budget Start
2014-09-15
Budget End
2019-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Type
University-Wide
DUNS #
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Marsh, William; Witten, Amanda; Stabenfeldt, Sarah E (2018) Exploiting Phage Display for Development of Novel Cellular Targeting Strategies. Methods Mol Biol 1831:71-94
Householder, Kyle T; DiPerna, Danielle M; Chung, Eugene P et al. (2018) pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma. Colloids Surf B Biointerfaces 166:37-44
Hickey, Kassondra; Stabenfeldt, Sarah E (2018) Using biomaterials to modulate chemotactic signaling for central nervous system repair. Biomed Mater 13:044106
Bharadwaj, Vimala N; Nguyen, Duong T; Kodibagkar, Vikram D et al. (2018) Nanoparticle-Based Therapeutics for Brain Injury. Adv Healthc Mater 7:
Bharadwaj, Vimala N; Rowe, Rachel K; Harrison, Jordan et al. (2018) Blood-brainbarrier disruption dictates nanoparticle accumulation following experimental brain injury. Nanomedicine 14:2155-2166
Addington, C P; Dharmawaj, S; Heffernan, J M et al. (2017) Hyaluronic acid-laminin hydrogels increase neural stem cell transplant retention and migratory response to SDF-1?. Matrix Biol 60-61:206-216
Dutta, D; Fauer, C; Hickey, K et al. (2017) Tunable delayed controlled release profile from layered polymeric microparticles. J Mater Chem B 5:4487-4498
Dutta, D; Hickey, K; Salifu, M et al. (2017) Spatiotemporal presentation of exogenous SDF-1 with PLGA nanoparticles modulates SDF-1/CXCR4 signaling axis in the rodent cortex. Biomater Sci 5:1640-1651
Dutta, Dipankar; Salifu, Mariama; Sirianni, Rachael W et al. (2016) Tailoring sub-micron PLGA particle release profiles via centrifugal fractioning. J Biomed Mater Res A 104:688-696
Bharadwaj, Vimala N; Lifshitz, Jonathan; Adelson, P David et al. (2016) Temporal assessment of nanoparticle accumulation after experimental brain injury: Effect of particle size. Sci Rep 6:29988

Showing the most recent 10 out of 14 publications