@article{2249f2c9dcf44cdcb3e9041e1e30ba72,
title = "Collagen fiber regulation in human pediatric aortic valve development and disease",
abstract = "Congenital aortic valve stenosis (CAVS) affects up to 10% of the world population without medical therapies to treat the disease. New molecular targets are continually being sought that can halt CAVS progression. Collagen deregulation is a hallmark of CAVS yet remains mostly undefined. Here, histological studies were paired with high resolution accurate mass (HRAM) collagen-targeting proteomics to investigate collagen fiber production with collagen regulation associated with human AV development and pediatric end-stage CAVS (pCAVS). Histological studies identified collagen fiber realignment and unique regions of high-density collagen in pCAVS. Proteomic analysis reported specific collagen peptides are modified by hydroxylated prolines (HYP), a post-translational modification critical to stabilizing the collagen triple helix. Quantitative data analysis reported significant regulation of collagen HYP sites across patient categories. Non-collagen type ECM proteins identified (26 of the 44 total proteins) have direct interactions in collagen synthesis, regulation, or modification. Network analysis identified BAMBI (BMP and Activin Membrane Bound Inhibitor) as a potential upstream regulator of the collagen interactome. This is the first study to detail the collagen types and HYP modifications associated with human AV development and pCAVS. We anticipate that this study will inform new therapeutic avenues that inhibit valvular degradation in pCAVS and engineered options for valve replacement.",
author = "Clift, {Cassandra L.} and Su, {Yan Ru} and David Bichell and {Jensen Smith}, {Heather C.} and Bethard, {Jennifer R.} and Kim Norris-Caneda and Susana Comte-Walters and Ball, {Lauren E.} and Hollingsworth, {M. A.} and Mehta, {Anand S.} and Drake, {Richard R.} and Angel, {Peggi M.}",
note = "Funding Information: The authors appreciate IRB-approved access to tissues from the Vanderbilt Heart Registry and Biorepository. Collagen SHG imaging was conducted at the Multiphoton Intravital and Tissue Imaging Core (University of Nebraska Medical Center) which receives support through the Nebraska Center for Nanomedicine (NCN) Center for Biomedical Research Excellence (Institutional Development Award, National Institute of General Medical Sciences of the National Institutes of Health, P30GM127200), state funds from the Nebraska Research Initiative, and institutionally by the UNMC Office of the Vice Chancellor for Research. Work by CLC is supported by a T32 from NHLBI (HL007260) and an F31 from NHLBI (HL156524). The Orbitrap Elite used in this research was funded by S10 D010731 (NIH/OD) to LEB. Microscopy data supported by the South Carolina COBRE in Oxidants, Redox Balance and Stress Signaling (GM 103542). Additional support was provided by the South Carolina Centers of Economic Excellence SmartState Program to RRD and ASM. Additional support to RRD, ASM and PMA by U01CA242096 (NCI). PMA appreciates support by 16GRNT31380005 (American Heart Association), R21CA240148 (NCI), P20GM103542 (NIH/NIGMS). The authors thank Professor Gary Hardiman for informatics discussion. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1038/s41598-021-89164-w",
language = "English (US)",
volume = "11",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}