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 #
5R01HL053354-15
Application #
8510705
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
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$439,101
Indirect Cost
$148,706
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
Kishore, Raj; Garikipati, Venkata Naga Srikanth; Gumpert, Anna (2016) Tiny Shuttles for Information Transfer: Exosomes in Cardiac Health and Disease. J Cardiovasc Transl Res 9:169-75
Kishore, Raj; Khan, Mohsin (2016) More Than Tiny Sacks: Stem Cell Exosomes as Cell-Free Modality for Cardiac Repair. Circ Res 118:330-43
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Zhou, Junlan; Cheng, Min; Boriboun, Chan et al. (2015) Inhibition of Sam68 triggers adipose tissue browning. J Endocrinol 225:181-9
Garikipati, Venkata Naga Srikanth; Verma, Suresh Kumar; Kishore, Raj (2015) The Nervous Heart: Role of Sympathetic Reinnervation in Cardiac Regeneration. Circ Res 117:980-1
Kishore, Raj; Benedict, Cynthia; Cheng, Zhongjian (2015) μ-Calpain as a Novel Target for Impairment of Nitric Oxide-Mediated Vascular Relaxation in Diabetes: A Mini Review. J Mol Genet Med 9:

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