Chair:

Dr. Steven R. Little

Department of Chemical and Petroleum Engineering, University of Pittsburgh

Committee Members:

 Dr. William R. Wagner

Department of Chemical and Petroleum Engineering, Department of Surgery, University of Pittsburgh

Dr. Heth R. Turnquist

Department of Surgery, University of Pittsburgh

Dr. Tagbo Niepa

Department of Chemical and Petroleum Engineering, University of Pittsburgh

Title: Engineering controllable release delivery systems to locally enhance regulatory T cells to Improve Myocardial Infarction

Abstract:

Myocardial infarction (MI – i.e. heart attack) is highly prevalent in America. Over 800,000 MIs occur each year, of which 20% are rehospitalizations due to subsequent MI. This is a significant burden on the health care system, amounting to annual hospital costs of over $12.1 billion dollars. Existing treatments for MI do not address the inflammatory or repair responses in the infarcted heart. Thus, there is an unmet clinical need to limit inflammatory and accelerate repair processes following MI. It is becoming apparent that regulatory T cells (Tregs) play a vital role in modulating the local immune response during MI and can significantly shape the repair and remodeling of tissue. Our group has previously developed degradable, polymer microspheres that can attract or induce Tregs. In collaboration with researchers at the University of Colorado that excel in the design of injectable hydrogels, we have developed an injectable Hydrogel to Enhance or Attract Regulatory T cells (iHEART) that combines injectable hydrogel technology with degradable, polymer microspheres.

In Aim 1, we manipulate encapsulating polymer properties to control polymer-protein interactions (acylation) in our microspheres facilitating more robust and reproducible release of bioactive cargo. Proposed experiments include characterizing our acylation inhibition using model proteins and evaluating how manipulating the polymer properties affect degradation rates of polymer microspheres. In Aim 2, we will utilize iHEART to attract naturally occurring Tregs to the infarcted heart in a mouse model of disease. Proposed experiments include characterization of the immune populations in the heart, quantification of functional changes in the tissue, and an evaluation of repair processes following iHEART treatment. Finally, in Aim 3 we propose to administer iHEART to induce Tregs, which are a rare cell type in the body, from more common CD4+ T cells entering the tissue. As in Aim 2, the proposed experiments will evaluate cardiac functional changes, repair, and immune population shifts with a particular focus on determining the phenotype and functional stability of the induced Tregs. For Aims 2 & 3, we will also utilize transgenic mice to probe, mechanistically, how iHEART-mediated Treg attraction or enhancement modulates the body’s response to heart attack to inform the development of novel therapeutic targets.