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@PHDTHESIS{Mina:1019101,
author = {Mina, Ioanna},
othercontributors = {Jankowski, Vera and Rauen, Thomas},
title = {{A}nalysis of type {I} collagen degradation fingerprint in
urine},
school = {Rheinisch-Westfälische Technische Hochschule Aachen},
type = {Dissertation},
address = {Aachen},
reportid = {RWTH-2025-08150},
pages = {13, 13 Seiten : Illustrationen},
year = {2025},
note = {Dissertation, Rheinisch-Westfälische Technische Hochschule
Aachen, 2025, Kumulative Dissertation},
abstract = {Collagen type I (COL1), composed of two alpha 1 (COL1A1)
and one alpha 2 (COL1A2) chains, is the most abundant
extracellular matrix (ECM) protein. Its excessive
accumulation in tissues, known as fibrosis, impairs organ
function, leads to organ failure, and is linked to major
chronic diseases, including chronic kidney disease(CKD).
While fibrosis is often attributed to increased collagen
expression, disruptions in collagen degradation remain
largely underexplored. To better understand the COL1
degradation process and how it is affected by sex and
fibrotic disease, we investigated naturally occurring COL1
degradation products (peptides) in urine using previously
generated anonymised peptidomics datasets acquired by
capillary electrophoresis coupled to mass spectrometry
(CE-MS). In the first study, 2008 datasets from healthy
individuals and patients with type II diabetes were used to
investigate the association of urinary peptides with sex.
Among the 90 sex-associated peptides identified,
56originated from 14 collagens, including 28 from COL1 (24
from COL1A1 and 4 from COL1A2). Notably, the abundance of
COL1A2 (n=4) and COL5A2 (n=2) fragments was consistently
decreased in males, while COL4A3(n=2) fragments were
consistently increased in males in comparison to females.
Cross-omics analysis with publicly available transcriptomics
data revealed the sex-biased expression of 9 collagen genes,
with COL1A2showing a consistently higher expression in males
across different tissues. The lower abundance of
urinaryCOL1A2 peptides in males, despite increased COL1A2
expression in male tissues, including the kidney cortex,
suggested a reduced COL1A2 degradation. Collectively, most
sex-specific changes in collagen peptides between males and
females could not be explained by differences in gene
expression and may instead reflect sex-biased collagen
degradation processes, potentially contributing to the
sex-specific manifestation of fibrotic diseases, including
CKD. In the second study, datasets from healthy individuals
(n=1131) and CKD patients (n=5585) were used to investigate
the degradation of COL1Α1 in detail. COL1A1 was selected
because its peptides are among the most affected by CKD and
are abundant in urine. Based on the hypothesis that many
collagen peptides are derived not from the entire, mature
collagen molecule but from (larger) collagen degradation
products, relationships between COL1A1 peptides containing
identical sequences were investigated, with the smaller
(offspring)peptide in each relationship being a possible
degradation product of the larger (parent) one. The
strongest correlations were found for relationships where
the parent differed by a maximum of 3 amino acids from the
offspring, indicating an exopeptidase-regulated stepwise
degradation process. Regression analysis showed that CKD
affects this degradation process. A comparison of datasets
from matched CKD patients and control individuals (n=612
each) showed that peptides at the start of the degradation
process were consistently downregulated in CKD, indicating
an attenuation of COL1A1 endopeptidase-mediated degradation.
However, as these peptides undergo further degradation,
likely mediated by exopeptidases, this downregulation can
become less significant or even reversed. Collectively,
these results support a stepwise degradation process
ofCOL1A1, where initial degradation by endopeptidases
produces larger fragments, which are then further degraded
by exopeptidases into progressively smaller fragments.
Notably, the initial COL1A1 fragments were consistently
downregulated in CKD, highlighting impaired
endopeptidase-mediated degradation. Together, the findings
from this dissertation provide a deeper understanding of the
COL1 degradation process and its differentiation by sex and
in fibrotic kidney disease. Insights into COL1A1 degradation
could provide potential therapeutic targets for treating
fibrosis. Additionally, urinary peptides could be used to
develop noninvasive, sex-specific biomarker panels for
fibrosis.},
cin = {531010-3 ; 932310},
ddc = {610},
cid = {$I:(DE-82)531010-3_20140620$},
pnm = {DisCo-I - Discovering Collagen I degradation process in
chronic diseases with fibrotic component (101072828)},
pid = {G:(EU-Grant)101072828},
typ = {PUB:(DE-HGF)11},
url = {https://publications.rwth-aachen.de/record/1019101},
}
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