Malformations and functional alterations of the lymphatic vasculature network promotes edema and fibrosis, which are some of the aggravating factors of cardiovascular diseases such as myocardial infarction. Recent studies suggested a beneficial role of lymphatic vessels in restoring cardiac function after cardiac injury; however, the mechanisms behind this improvement remain unknown. My preliminary data using a variety of available animal models with defective lymphatics supports such proposal. In addition, I also identified a reduction in cardiac size in mouse embryos with a reduced or missing lymphatic vasculature. Therefore, my long-term goal is to gain a better understanding of the cardiac and lymphatic network cross-talk during heart development and in disease models as a tool to help prevent and to develop therapeutic approaches for cardiac diseases. Accordingly, my research proposal and career development plan for this American Heart Association Career Development Award application is focused in accomplishing these goals. The central hypothesis of this research proposal is that cardiac LECs promote cardiomyocyte survival during development and after cardiac injury, and that they contribute to enhanced cardioprotection through paracrine signals. To validate this hypothesis I propose two Specific Aims: Aim 1 will investigate how LECs regulate heart development by characterizing cardiac defects in mouse models with defective or reduced lymphatic network. This approach will be complemented by the use of RNA-seq analysis to identify transcriptional changes in genes and pathways altered in cardiomyocytes isolated from those mutant mouse strains. Aim 2 will focus in understanding how LECs modulate cardiomyocyte survival after heart injury using models of chronic myocardial infarction using again mouse models with defective and reduced lymphatics. I also found that adding LEC-conditioned media to human induced pluripotent stem cell (hiPSC)-derived CMs (hiPSC-CMs) greatly increased hiPSC-CM survival and prevent CM apoptosis from hypoxia, a result suggesting that LECs promote CM survival. Therefore, in Aim 2 I will also evaluate the possible paracrine effects by which LECs promote CM survival using in vitro assays. Finally, I also include a 3-year career development plan to prepare me for an independent academic position. For this application, I assembled an expert mentorship team with expertise in basic and clinically oriented lymphatic and cardiac biology that will provide me with in-depth training and mentoring. Overall, this award will facilitate my transition toward an independent research program.
|Effective start/end date||7/1/18 → 6/30/21|
- American Heart Association (18CDA34110356)