Approximately 25% of myocardial infarction (MI) patients progress to develop congestive heart failure, which has a 50% 5-year mortality rate. The goal of this project is to understand post-MI roles of the macrophage by establishing and validating an in silico computational model of the temporal evolution of macrophage polarization. Our preliminary results demonstrate that macrophages proceed through a series of polarization profiles over the first 7 days post-MI and that modifying macrophage polarization can alter remodeling of the left ventricle (LV). We hypothesize that macrophages undergo a temporal phenotype evolution to coordinate the post-MI LV remodeling phenotype.
Our specific aims are: 1) construct an in silico computational model that simulates macrophage polarization patterns over the post-MI time course; 2) perturb endogenous IL-1 signaling pathway to evaluate the system and optimize model robustness; and 3) examine exogenous influences to evaluate model predictability. The innovation of this proposal lies in both the concept that macrophages regulate remodeling as a continuum of phenotypes and that integration of experimental and computational approaches will allow us to establish a predictive computational tool. The potential outcome of these studies will be 1) the development of a computational tool to simulate macrophage polarization post-MI; 2) the identification of macrophage polarization markers that predict LV remodeling outcomes; and 3) recognition of key inflammatory mechanisms that can be therapeutically modulated to regulate macrophage polarization.
Patients who have had a heart attack are at high risk to develop congestive heart failure, and the 5 year mortality rate for heart failure is 50%. The macrophage is a major cell that coordinates wound healing in the heart after a heart attack, and modifying the macrophage response may improve outcomes. The main objective of this grant is to construct a simulation of the macrophage response to a heart attack, which may help us to develop therapies that prevent the development of heart failure.
| Lindsey, Merry L; Gray, Gillian A; Wood, Susan K et al. (2018) Statistical considerations in reporting cardiovascular research. Am J Physiol Heart Circ Physiol 315:H303-H313 |
| Mouton, Alan J; DeLeon-Pennell, Kristine Y; Rivera Gonzalez, Osvaldo J et al. (2018) Mapping macrophage polarization over the myocardial infarction time continuum. Basic Res Cardiol 113:26 |
| Lindsey, Merry L; Jung, Mira; Yabluchanskiy, Andriy et al. (2018) Exogenous CXCL4 Infusion Inhibits Macrophage Phagocytosis by Limiting CD36 Signaling to Enhance Post-myocardial Infarction Cardiac Dilation and Mortality. Cardiovasc Res : |
| Lindsey, Merry L (2018) Reg-ulating macrophage infiltration to alter wound healing following myocardial infarction. Cardiovasc Res 114:1571-1572 |
| DeLeon-Pennell, Kristine Y; Mouton, Alan J; Ero, Osasere K et al. (2018) LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling. Basic Res Cardiol 113:40 |
| Lindsey, Merry L; Kassiri, Zamaneh; Virag, Jitka A I et al. (2018) Guidelines for measuring cardiac physiology in mice. Am J Physiol Heart Circ Physiol 314:H733-H752 |
| Lindsey, Merry L; Jung, Mira; Hall, Michael E et al. (2018) Proteomic analysis of the cardiac extracellular matrix: clinical research applications. Expert Rev Proteomics 15:105-112 |
| Mouton, Alan J; Rivera Gonzalez, Osvaldo J; Kaminski, Amanda R et al. (2018) Matrix metalloproteinase-12 as an endogenous resolution promoting factor following myocardial infarction. Pharmacol Res 137:252-258 |
| DeLeon-Pennell, Kristine Y; Iyer, Rugmani Padmanabhan; Ma, Yonggang et al. (2018) The Mouse Heart Attack Research Tool 1.0 database. Am J Physiol Heart Circ Physiol 315:H522-H530 |
| Bloksgaard, Maria; Lindsey, Merry L; Martinez-Lemus, Luis A (2018) Extracellular Matrix in Cardiovascular Pathophysiology. Am J Physiol Heart Circ Physiol : |
Showing the most recent 10 out of 169 publications
