Diabetes is a near-pandemic disease with substantial morbidity associated with non-healing foot ulcers (DFUs). Impaired angiogenesis is a limiting factor for wound healing in diabetics, and thus therapeutic vascularization approaches have been applied to treat DFUs. However, cell-based therapeutic vascularization has yet to be validated in large clinical trials and conventional drug and protein treatments have largely failed or been disappointing. Therefore, the development of improved therapeutic vascularization approaches to treat DFUs would fill a critical clinical need. One emerging strategy for molecular therapeutic vascularization is engagement of the ErbB receptor family with Neuregulin-1 (NRG). Though well studied in cancer and many organ systems, relatively little is known about the role of NRG/ErbB signaling in vascularization. NRG is a known endothelial cell mitogen and has been shown to be a crucial mediator of the angiogenic response to ischemia in a mouse model. NRG splice variants, as well as other proteins in the NRG subfamily, are also potential endothelial effectors via their high binding affinity to receptors ErbB3 and ErbB4. Overwhelming evidence indicates that ErbB receptors initiate signaling following dimerization, most often with another ErbB family member. Given that there are four known ErbB receptors, one of which (ErbB2) does not have a known ligand and is thought to exist in a quasi-activated state, splice variants of NRG are capable of inducing signaling through multiple ErbB dimers or oligomers, each set of which may activate a unique pathway. Thus, the role of NRG/ErbB signaling in vascularization is unclear and the potential to maximize the efficacy of ErbB ligands in therapeutic vascularization remains unrealized. In this application, the role of ErbB receptors in vascularization will be explored by pursuing three specific aims.
Aim 1 will test the hypothesis that biasing of endothelial ErbB signaling can regulate endothelial cell phenotype. Experiments in Aim 2 will test the hypothesis that local delivery of ErbB receptor ligands can stimulate therapeutic vascularization in vivo via an endothelial ErbB receptor-mediated mechanism.
In Aim 3, the hypothesis that skin substitute engraftment can be enhanced via integration with local delivery of ErbB receptor ligands will be tested. At the conclusion of this work, significant steps towards clarifying the role of ErbB receptors in vascularization and determining their potential as therapeutic targets in diabetic wound healing will have been taken. Furthermore, this project has broader implications; the therapeutic strategies developed here have the potential to serve as an enabling technology in the field of tissue engineering. Relevance to Public Health - Therapeutic vascularization via engagement of ErbB receptors is a novel, promising approach to decreasing morbidity and mortality associated with non-healing diabetic foot ulcers. Here, the use of new technology and strategies to develop an improved mechanistic understanding of ErbB receptors in vascularization is proposed. This advance would enable new therapeutic approaches in diabetic wound healing.

Public Health Relevance

Therapeutic vascularization via engagement of ErbB receptors is a novel, promising approach to decreasing morbidity and mortality associated with non-healing diabetic foot ulcers. Here, the use of new technology and strategies to develop an improved mechanistic understanding of ErbB receptors in vascularization is proposed. This advance would enable new therapeutic approaches in diabetic wound healing.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL112905-05
Application #
8849958
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gao, Yunling
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2015-06-01
Budget End
2017-05-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Type
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
McKay, Ryan; Ghodasra, Monil; Schardt, John et al. (2018) A platform of genetically engineered bacteria as vehicles for localized delivery of therapeutics: Toward applications for Crohn's disease. Bioeng Transl Med 3:209-221
Lamichhane, Tek N; Jay, Steven M (2018) Production of Extracellular Vesicles Loaded with Therapeutic Cargo. Methods Mol Biol 1831:37-47
Patel, Divya B; Santoro, Marco; Born, Louis J et al. (2018) Towards rationally designed biomanufacturing of therapeutic extracellular vesicles: impact of the bioproduction microenvironment. Biotechnol Adv 36:2051-2059
Li, Lei; Jay, Steven M; Wang, Yan et al. (2017) IL-12 stimulates CTLs to secrete exosomes capable of activating bystander CD8+ T cells. Sci Rep 7:13365
Patel, Divya B; Gray, Kelsey M; Santharam, Yasasvhinie et al. (2017) Impact of cell culture parameters on production and vascularization bioactivity of mesenchymal stem cell-derived extracellular vesicles. Bioeng Transl Med 2:170-179
Lamichhane, Tek N; Leung, Christopher A; Douti, Lampouguin Yenkoidiok et al. (2017) Ethanol Induces Enhanced Vascularization Bioactivity of Endothelial Cell-Derived Extracellular Vesicles via Regulation of MicroRNAs and Long Non-Coding RNAs. Sci Rep 7:13794
Jay, Steven M; Vunjak-Novakovic, Gordana (2017) Extracellular Vesicles and their Versatile Roles in Tissue Engineering. Tissue Eng Part A :
Kuwahara, Go; Hashimoto, Takuya; Tsuneki, Masayuki et al. (2017) CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation. Arterioscler Thromb Vasc Biol 37:1147-1156
Schardt, John S; Oubaid, Jinan M; Williams, Sonya C et al. (2017) Engineered Multivalency Enhances Affibody-Based HER3 Inhibition and Downregulation in Cancer Cells. Mol Pharm 14:1047-1056
Lamichhane, Tek N; Jeyaram, Anjana; Patel, Divya B et al. (2016) Oncogene Knockdown via Active Loading of Small RNAs into Extracellular Vesicles by Sonication. Cell Mol Bioeng 9:315-324

Showing the most recent 10 out of 17 publications