[R03] Elucidation of fibrotic signatures after regenerating and non-regenerating myocardial infarction
Ente: National Heart Lung and Blood Institute
Scadenza: 2028-03-31
Importo max: 246.750 EUR
Paese: US
Descrizione
Cardiac fibrosis is the deposition of extracellular matrix (ECM) components in the heart that occurs after various
injuries to the heart muscle, such as a myocardial infarction (MI). After an MI, fibrosis can be a double-edged
sword: in the early stage, cardiac fibrosis can be protective by preventing rupture of the weakened heart muscle.
However, over time, cardiac fibrosis is largely deleterious as it can increase myocardial stiffness and compromise
contractile function. Currently, we have no treatments for cardiac fibrosis, even though it is a common feature of
ischemic heart disease, diabetes mellitus, and aging. In stark contrast to the adult heart, the neonatal heart is
capable of regenerating after injury in the first few days of life. The regenerative phase after neonatal injury is
notable for the presence of cardiac fibrosis, which is resolved and presumably resorbed within the first month of
life. How the neonatal heart can resolve fibrosis remains obscure. We hypothesize that studying the neonatal
heart for fibrosis-resolving mechanisms could help discover anti-fibrotic therapies for the adult heart. As a
physician-scientist and Assistant Professor in the Division of Cardiology at Columbia University Medical Center,
I have developed the current R03 proposal to elucidate the differences between the neonatal and adult heart
with respect to the fibrotic response after MI. This proposal will leverage the training I received through my K08
award to characterize the role of secreted proteins and to develop mouse models of proximity proteomics to label
the secretome. In Aim 1, we will generate a new genetic mouse model that can label the secretome of cardiac
fibroblasts in vivo through biotinylation, namely through targeting a biotin ligase (TurboID) to the endoplasmic
reticulum specifically in the cardiac fibroblast lineage. Using this model, we will profile the factors elaborated by
cardiac fibroblasts in the uninjured adult heart as a benchmarking strategy. In Aim 2, we will apply this model to
the neonatal and adult heart after MI. The resulting hits will be bioinformatically filtered by protein class. The
class of secretory proteins will be compared pairwise between the neonatal and adult hearts to determine how
expression of ECM proteins, proteases, and ligands of canonical pro-fibrotic signaling pathways differ at distinct
time points. The proposed experiments will fill a critical knowledge gap in the field regarding the role of fibrosis
in neonatal heart regeneration. Successful completion of this project will produce preliminary data for an R01
grant that will test whether mechanisms that resolve fibrosis in the neonatal heart can achieve the same goal in
the adult heart.
Istituzione: COLUMBIA UNIVERSITY HEALTH SCIENCES
PI: Shah Rukh Ali
Progetto: 1R03HL185266-01
Settori: National Heart Lung and Blood Institute
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