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Predicting Post-Myocardial Infarction Matrix Responses

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After myocardial infarction (MI), the matrix response largely dictates how long you will live. Most heart failure after MI occurs a few months thereafter, aligning with the time fibroblasts require to deposit a scar. This dissertation focuses on how neonatal mammals can regenerate their hearts after MI and how we can interrogate these molecular hypotheses in-vitro. Chapter 1 provides an overview of the infarction cascade, known cellular and biomolecular contributions to inflammation, and the composition and structure of the extracellular matrix. Chapter 2 discusses how neonatal and adult cardiac healing differ. RNA-seq datasets were mined to provide insight to key pathways, receptors, and ligands that uniquely contribute to adult scar formation. Chapter 3 establishes an induced pluripotent stem cell (iPSC) to cardiac fibroblast (CF) differentiation through the epicardial lineage. Marker expression, matrix assembly, stress response, and chromatin architecture relative to other contemporary protocols and primary cells are characterized. Chapter 4 tests the central informatic hypotheses generated in chapter 2, particularly with respect to sterile inflammatory ligands (TGF-β, low molecular weight hyaluronic acid, and angiotensin II). It also investigates how these stress responses manifest in patients with single nucleotide polymorphisms (SNPs) in a long noncoding RNA (lncRNA) that worsen cardiovascular outcomes clinically. Chapter 5 is an extended discussion of the cumulative results, significance, and potential future approaches to cardiac fibrosis modeling. The discoveries herein demonstrate a novel method of reductionist fibrotic modeling in-vitro, highlight central fibrotic pathways, and suggest therapeutic targets.

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This item is under embargo until June 27, 2024.