Student: Suraj Bastola
Project: Matrix regenerative nanotherapeutics for aortic aneurysm repair
View: Research Poster (PDF) | Presentation (YouTube)
Department: Bioengineering
Advisor: Anand Ramamurthi
Abstract
Abdominal Aortic Aneurysms (AAA) are localized, rupture-prone expansions of the aortic wall characterized by upregulated inflammatory cytokine production, vascular smooth muscle cells (VSMCs) apoptosis, chronic proteolytic breakdown of ECM structures (collagen and elastic fibers) by matrix metalloproteases (MMPs), loss of nitric oxide (NO) signaling, and phenotypic modulation of VSMCs. Previous studies have shown that Nitric Oxide (NO) inhibits proteolytic enzymes MMPs. We examined dose (100 pM-100 nM) specific effects of Sodium Nitroprusside (SNP), a NO donor drug, in downregulating MMPs and upregulating elastic fiber assembly, crosslinking and maturation in a cytokine-injury culture model of human AAA VSMCs. We will subsequently release the drug from actively targeted, biodegradable polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) which are surface-functionalized to impart anti-proteolytic and pro-elastogenic properties separate from the released drug. Our PCR data shows SNP to significantly downregulate MMP2 and collagen type III, and significantly upregulate elastin synthesis, LOX (elastin crosslinking enzyme), and TIMP2 (MMP 2 inhibitor) genes (p<0.05). The TIMP2/ MMP2 ratio was ~5 fold and the elastin/ collagen III gene expression ratio were 3-fold higher at100nM of SNP (p<0.05) vs. drug-free control cells. Western blots showed significant decreases in MMP2 protein vs. controls. While our WB studies are yet ongoing, our RT-PCR data indicates clear dose-specific benefits of SNP with gene expression trends suggestive of enhanced elastic fiber assembly, crosslinking and decreased elastolytic activity, particularly at doses of 100 nM or higher. This work can potentially lead to a minimally-invasive regenerative therapy to reverse elastin damage in AAAs.
About Suraj Bastola
Suraj Bastola is a biomedical engineer. In his undergrad, Bastola has worked on research entitled “Effect of pulsating magnetic field and anti-cancer drugs in non-small cell lung cancer.” Bastola's passion is to dedicate myself to the research of different pathophysiology and learn their molecular mechanism to study various ways of stopping or reversing them for normal functioning of the body. In abdominal aortic aneurysms (AAAs), elastic fibers are chronically degraded by overexpressed proteases. The diseased and healthy smooth muscle cells in the aortic wall are unable to regenerate elastin as they regenerate collagen. Elastin here is the missing link in AAAs repair. Thus, Bastola's goal is to guide the functional regeneration of elastin to restore aortic function.