Critical limb ischemia (CLI) imposes a major public health burden, resulting in high rates of death and disability. Thus far no medical therapy has been shown to ameliorate CLI. The goal of this proposal is to develop innovative therapeutic approaches for CLI with the use of endothelial progenitor cell (EPC) based therapies augmented by novel biomaterials-based approaches. These studies will investigate 3 novel bioactive peptide amphiphiles (PA) in combination with direct EPC injections or alone for repair ischemic limb tissue. One of the novels, bioactive motifs developed in our lab includes motifs that foster cell adhesion through a domain containing Arg-Gly-Asp-Ser (RGDS) we will extend preliminary data generated in our labs indicating that RGDS-presenting PA nanostructures enhance EPC function and investigate certain mechanisms responsible for these effects in models of critical limb ischemia. Another approach that we have explored is provision of an angiogenic signal with a vascular endothelial growth factor (VEGF) mimetic epitope. We will extend our preliminary in vitro and in vivo studies to evaluate the effect of VEGF-mimetic PA to improve perfusion in ischemic limb tissue. Abundant prior data from our lab has established that the morphogen Shh is activated post-natally in response to ischemia and that exogenous Shh can affect ischemic tissue repair. We have recently developed a novel, inject able liquid crystalline PA that provides sustained, local release of Shh protein and will investigate the use of this material to treat models of critical limb ischemia.

Public Health Relevance

Critical limb ischemia (CLI) imposes a major public health burden, resulting in high rates of death and disability. Thus far no medical therapy has been shown to ameliorate CLI. The goal of this proposal is to develop innovative therapeutic approaches for CLI with the use of novel biomaterials-based approaches to enhance the effects of endothelial progenitor cell (EPC) based therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053354-14
Application #
8299009
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Gao, Yunling
Project Start
1995-01-01
Project End
2016-06-30
Budget Start
2012-07-13
Budget End
2013-06-30
Support Year
14
Fiscal Year
2012
Total Cost
$462,070
Indirect Cost
$156,158
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Tongers, Jörn; Webber, Matthew J; Vaughan, Erin E et al. (2014) Enhanced potency of cell-based therapy for ischemic tissue repair using an injectable bioactive epitope presenting nanofiber support matrix. J Mol Cell Cardiol 74:231-9
Kishore, Raj; Verma, Suresh K; Mackie, Alexander R et al. (2013) Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac miRNA-155 modulates fibrotic response in diabetic hearts. PLoS One 8:e60161
Ghosh, Asish K; Murphy, Sheila B; Kishore, Raj et al. (2013) Global gene expression profiling in PAI-1 knockout murine heart and kidney: molecular basis of cardiac-selective fibrosis. PLoS One 8:e63825
Jujo, Kentaro; Ii, Masaaki; Sekiguchi, Haruki et al. (2013) CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism. Circulation 127:63-73
Mackie, Alexander R; Krishnamurthy, Prasanna; Verma, Suresh K et al. (2013) Alcohol consumption negates estrogen-mediated myocardial repair in ovariectomized mice by inhibiting endothelial progenitor cell mobilization and function. J Biol Chem 288:18022-34
Zhou, Junlan; Cheng, Min; Wu, Min et al. (2013) Contrasting roles of E2F2 and E2F3 in endothelial cell growth and ischemic angiogenesis. J Mol Cell Cardiol 60:68-71
Masuda, Haruchika; Asahara, Takayuki (2013) Clonogenic assay of endothelial progenitor cells. Trends Cardiovasc Med 23:99-103
Nishimura, Yukihide; Ii, Masaaki; Qin, Gangjian et al. (2012) CXCR4 antagonist AMD3100 accelerates impaired wound healing in diabetic mice. J Invest Dermatol 132:711-20
Gupta, Rajesh; Losordo, Douglas W (2011) Cell therapy for critical limb ischemia: moving forward one step at a time. Circ Cardiovasc Interv 4:2-5
Sahoo, Susmita; Klychko, Ekaterina; Thorne, Tina et al. (2011) Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ Res 109:724-8

Showing the most recent 10 out of 104 publications