[K99] Exploring the role of Hedgehog pathway-Primary cilia axis in human lung alveologenesis and disease
Ente: National Heart Lung and Blood Institute
Scadenza: 2027-07-31
Importo max: 156.168 EUR
Paese: US
Descrizione
Project Summary/ Abstract
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of prematurity, characterized by
defective gas exchange area, due to reduced alveolar surface. The alveolar epithelium is composed of squamous
alveolar epithelial type 1 cells (AT1), which cover more than 90% of the alveolar surface, and cuboidal alveolar
epithelial type 2 (AT2) cells that possess stem and progenitor cell capabilities as demonstrated by their ability to
self-renew, maintain the AT2 pool, and differentiate into AT1 during alveolarization and following lung injury. The
alveolar epithelium serves as a physical barrier against environmental stimuli. Alveolar formation in humans
occur in utero and is regulated by multiple cellular and molecular processes, involving proliferation,
differentiation, and epithelial-mesenchymal crosstalk. The Hedgehog (HH) pathway plays an important role in
orchestrating these events and its deregulation can result in defective lung development, thus leading to
diseases such as BPD. Aberrant HH signaling is implicated in BPD as well as various adult lung diseases, such
as asthma and COPD. We recently described that the HH signaling plays an important role in early human lung
development. The HH pathway ligand, Sonic Hedgehog (SHH) regulates progenitor cell interactions in the airway
and alveolar compartments during lung development. Our previously generated scRNAseq data demonstrate a
continuous increase of SHH expression during human lung development. Additionally, the HH pathway activator
(PTCH1) is highly expressed during early lung development, coinciding with the expansion of the progenitor cell
pool, while the inhibitor (HHIP) is highly expressed during progenitor differentiation. These observations suggest
that early activation of the HH pathway is essential in early lung development, whereas its inhibition promotes
alveologenesis. The HH pathway is regulated by sensory organelles, called primary cilia (PC), which play an
important role in the transduction of the HH signaling. The presence and proper function of PC are known to be
essential for the activation and modulation of the HH pathway during various stages of lung development. We
recently demonstrated a dysregulation of the HH pathway and PC in COPD, and our preliminary data suggest
disruption of these elements in BPD. Therefore, we hypothesize that a HH/primary cilia signaling axis is crucial
during alveologenesis, facilitating the maturation of AT2 cells. To test this hypothesis, we will 1) Investigate the
role of HH signaling in the maturation of alveolar epithelial cells (K99), 2) Investigate the interaction between PC
and HH signaling in alveologenesis (K99/R00), and 3) Assess the interplay between the HH pathway and PC in
BPD (R00). The proposed career development plan is designed to equip the PI with unique skill sets, expand
knowledge base and research experience to becoming a productive and independent investigator researcher in
the fie
Istituzione: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
PI: RANDA SONIA BELGACEMI
Progetto: 5K99HL177341-02
Settori: National Heart Lung and Blood Institute
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.