Research has implications for more common
pulmonary disorders
PHOENIX, June 19,
2024 /PRNewswire/ -- According to a study
published in Nature Communications, research conducted at
the Phoenix Children's Research Institute at the University of Arizona College of Medicine —
Phoenix, shows how frequent
non-coding FOXF1 gene deletions that interfere with
important DNA regulatory regions, called enhancers, can lead to
Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins
(ACDMPV), a rare, lethal, genetic lung disease which causes
respiratory failure in newborns and infants.
The FOXF1 protein is critically important in pulmonary vascular
development, specifically responsible for the extension and
branching of airways and blood vessels in the developing lung.
"Prior to this study, we knew deletions and mutations in the
FOXF1 gene locus can result in ACDMPV, so our goal was
to identify FOXF1 enhancers associated with the disease so we can
diagnose it more precisely in newborn babies," said Vlad Kalinichenko, MD, PhD, internationally
renowned lung development and regeneration researcher and director
of the Phoenix Children's Research Institute at the University of Arizona College of Medicine –
Phoenix.
This study, conducted in collaboration with Cincinnati
Children's Hospital Medical Center, identified four upstream
enhancers in the FOXF1 gene locus — FOXF1 Expression
in the Lung 1, 2, 3 and 4. It further showed these elements
stimulate cell-specific FOXF1 expression in pulmonary
endothelium and stromal cells, such as fibroblasts and pericytes.
Pulmonary endothelial cells are essential to the development of
alveoli, the tiny branches of air tubes in the lungs responsible
for the exchange of oxygen and carbon dioxide in the bloodstream.
Likewise, pulmonary stromal cells are also important to lung
development and are a crucial component of overall lung
structure.
Since many non-coding deletions in or near the FOXF1 gene
locus cause ACDMPV, identifying specific pathogenic FOXF1 enhancers
— that are critical for lung development — is important to
understand and diagnose ACDMPV. This work could also enable better
genetic screening for the disease, which currently relies primarily
on exome DNA sequencing.
"This study demonstrates four specific FOXF1
enhancers play critical roles in the development of ACDMPV and
resolves an important clinical question regarding why frequent
non-coding FOXF1 deletions that interfere with endothelial
and mesenchymal enhancers can lead to this lethal disease," said
Dr. Kalinichenko. "Identifying mutations in the FOXF1 gene
locus sooner will be critical for accurate genetic diagnosis of
this severe congenital disease. As we continue to gain additional
insight into how genes work, it will improve our capabilities to
implement effective therapeutic interventions in more common
pulmonary disorders of newborns and infants, such as
bronchopulmonary dysplasia and congenital diaphragmatic
hernia."
The Phoenix Children's Research Institute at the University of Arizona College of Medicine –Phoenix
launched in May 2023, formalizing a
longstanding research collaboration between the health system and
the University of Arizona College of
Medicine – Phoenix. The Research
Institute includes more than 700 active studies, 640 research
investigators and 90 research staff members, including research
scientists, associates, biostatisticians, pharmacists, nurses and
coordinators. Scientists engage in research across multiple
clinical disciplines,
including cancer, neurology, cardiology, pulmonology
and more.
About Phoenix Children's
Phoenix Children's is one of the nation's largest
pediatric health systems. It comprises Phoenix Children's Hospital
– Thomas Campus, Phoenix Children's Hospital – East Valley
Campus, Phoenix Children's – Avondale Campus, Phoenix
Children's – Arrowhead Campus, four pediatric specialty and urgent
care centers, 12 community pediatric practices, 20 outpatient
clinics, two ambulatory surgery centers and seven community-service
outpatient clinics throughout the state of Arizona. The system
provides world-class inpatient, outpatient, trauma, emergency and
urgent care, and has been serving children and families for 40
years. Phoenix Children's Care Network includes more than 1,175
pediatric primary care providers and specialists who deliver care
across more than 75 subspecialties. Alongside our colleagues,
collaborators and communities, we're elevating pediatric care,
education and innovation, so we can all grow healthier together.
For more information, visit phoenixchildrens.org.
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SOURCE Phoenix Children's