Phd Proposal by Michael Sayegh

Event Details
  • Date/Time:
    • Wednesday September 18, 2019
      9:00 am - 10:00 am
  • Location: EUH Hurst Conference Room (E450)
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Summaries

Summary Sentence: A biomaterials approach to inhibit neutrophils extracellular traps in cardiac ischemia and reperfusion injury

Full Summary: No summary paragraph submitted.

Michael Sayegh

BME PhD Proposal Presentation

 

Date: September 18, 2019

Time: 9:00-10:00 AM

Location: EUH Hurst Conference Room (E450)

 

Committee Members:

Rebecca D. Levit, MD (Advisor)

W. Robert Taylor, MD PhD

Andrés J. García, PhD 

Rabindra Tirouvanziam, PhD

Nick Willett, PhD

 

Title: A biomaterials approach to inhibit neutrophils extracellular traps in cardiac ischemia and reperfusion injury

 

Thesis proposal abstract:

Despite great advances, ischemic heart disease is still the leading cause of death worldwide, and novel interventions are needed to improve outcomes. This proposal takes a dual investigative and therapeutic approach to neutrophil extracellular trap (NET) involvement in myocardial ischemia and reperfusion injury (MI/R). In Aim 1, we will parse the specific cell types among the main cardiac cell populations that are susceptible to NET-induced damage. We then study the effect of introducing NETs into a healthy heart on contraction, immune infiltration, and subsequent fibrosis. Finally, we seek a mechanism of NET damage by screening for cytokine responses and Toll-like receptor (TLR) mediators. In Aim 2, we engineer an adenosine delivery vehicle to inhibit NETosis a priori. Considering its dose-limiting side-effects and short half-life in circulation, adenosine is impractical to deliver directly. Instead, we embed an enzyme, CD73, that catalyzes the rate-limiting step in endogenous adenosine formation, in a polyethylene glycol 4-maleimide (PEG-4MAL) hydrogel, and test parameters of the gel and variations on the cargo, to evaluate their function in producing adenosine. Then we use our adenosine delivery tool, the CD73 functionalized hydrogel, to inhibit reactive oxygen species (ROS) production and NETosis in vitro. In Aim 3, we propose to deliver the best performing gels in vivo and test their ability to augment cardiac adenosine. We will apply the gel onto a rat model of MI/R and measure its ability to reduce scar size and preserve cardiac function, in correlation with decreased immune infiltration and MI/R-induced NETosis, and improved vascular perfusion. 

Therefore, by increasing the availability of a NET inhibitor and anti-inflammatory drug, adenosine, from substrate released in myocardial ischemic damage, we aim to reduce the negative sequelae of MI/R, and establish proof of concept for a clinically translatable biomaterial.

 

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Graduate Studies

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Phd proposal
Status
  • Created By: Tatianna Richardson
  • Workflow Status: Published
  • Created On: Sep 5, 2019 - 9:56am
  • Last Updated: Sep 5, 2019 - 9:56am