Project Details
Description
PROJECT SUMMARY Congenital heart disease (CHD) is a significant cause of neonatal mortality and morbidity
worldwide. Defects in the aortic arch artery (AAA) and its major branches are among the most severe
malformations that cause CHD. The AAA and its branches arise through the asymmetrical remodeling of the
three bilaterally symmetrical pairs of the pharyngeal arch arteries (PAAs), 3, 4, and 6. Defects in the left 4th PAA
are particularly devastating, leading to the interruption of the aortic arch type B (IAA-B). IAA-B disrupts the
systemic circulation and is lethal after birth. The genetic causes of IAA-B are mostly unknown, underscoring a
critical need to understand genes and mechanisms regulating the formation of the left 4th PAA. PAA formation is
a multi-step process: PAA endothelial cell (EC) progenitors arise in the second heart field (SHF) by E7.5 and
populate pharyngeal arches within the next two days, culminating in the formation of a plexus of small SHF-
derived blood vessels between by E10.0 in the 4th arch. Following its formation, the EC plexus gradually remodels
by merging in the middle of the 4th arch into one large vessel, the 4th PAA. The deletion of Fn1 or integrin a5b1
in the Isl1 lineages results in the defective formation of the right and left 4th PAA and leads to IAA-B. My lab has
demonstrated that cell-ECM interactions regulated by Fn1 and integrin a5b1 function reiteratively, at multiple
stages to regulate the 4th PAAs’ formation and remodeling in a cell-type-specific manner. In this grant, we present
data implicating Fn1 and integrin a5b1 in maintaining the ipsilateral patterning of the SHF-derived vasculature
in the pharynx at E9.5. Our data show that the deletion of Fn1 or integrin a5b1 in the Isl1 lineage disrupts
symmetrical allocation of SHF-derived cells to the left and right pharyngeal arches, causing an imbalance in the
number of SHF-derived cells on the left vs. the right. At a later stage, between E10 and E10.75, Fn1 and integrin
a5b1 regulate vascular patterning by mediating the remodeling of the pharyngeal EC plexus into the 4th PAA.
Our published data show that Fn1 and integrin a5b1 mediate the plexus-to-PAA remodeling in an EC-non-cell-
autonomous manner by regulating the expression of negative vascular guidance cues and the activation of
VEGFR2 and Erk1/2 in the 4th arch. To determine the mechanisms by which Fn1 and integrin a5b1 regulate the
patterning of SHF-derived vasculature, we will use live imaging, quantitative immunofluorescence microscopy,
genetic epistasis analysis, and single-cell RNAseq to test two hypotheses 1) that Fn1 and integrin a5b1
expressed in the Isl1 lineage maintain the balanced allocation of SHF-derived cells in the pharynx by regulating
ECM assembly and ipsilateral SHF cell migration and 2) that Fn1 and integrin a5b1 regulate plexus-to-PAA
remodeling by modulating the expression of EC guidance cues and the activation of Erk1/2. Completing the
proposed studies will provide essential insights into the functions of cell-ECM interactions in the development of
SHF-derived vasculature and CHD pathogenesis.
Status | Active |
---|---|
Effective start/end date | 7/1/10 → 8/31/25 |
Funding
- National Heart, Lung, and Blood Institute: $365,211.00
- National Heart, Lung, and Blood Institute: $436,807.00
- National Heart, Lung, and Blood Institute: $86,665.00
- National Heart, Lung, and Blood Institute: $390,000.00
- National Heart, Lung, and Blood Institute: $478,279.00
- National Heart, Lung, and Blood Institute: $390,000.00
- National Heart, Lung, and Blood Institute: $335,835.00
- National Heart, Lung, and Blood Institute: $41,401.00
- National Heart, Lung, and Blood Institute: $445,721.00
- National Heart, Lung, and Blood Institute: $533,329.00
- National Heart, Lung, and Blood Institute: $383,625.00
- National Heart, Lung, and Blood Institute: $445,721.00
- National Heart, Lung, and Blood Institute: $523,266.00
- National Heart, Lung, and Blood Institute: $375,953.00
- National Heart, Lung, and Blood Institute: $387,375.00
- National Heart, Lung, and Blood Institute: $35,531.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.