Hypoxia-inducible factor(HIF)-driven modulation of alveolar regeneration - PROJECT SUMMARY The current paradigm of Idiopathic pulmonary fibrosis (IPF) pathogenesis implicates recurrent injury and dysfunctional repair of the alveolar epithelium which results in fibrotic lung remodeling and loss of functional blood-gas exchange units. Current IPF treatments modestly slow disease progression by attenuating collagen production by fibroblasts, but no available therapies stabilize disease nor facilitate functional lung repair. Our overarching hypothesis is that therapies modulating upstream disease mechanisms to promote functional alveolar repair could be transformative disease-modifying treatments for patients with IPF and other chronic lung diseases. The loss of normal alveolar blood-gas barrier forming Alveolar Type 1 (AT1) and surfactant- producing Alveolar Type 2 (AT2) cells has long been recognized in IPF and supported the concept that dysfunction of epithelial progenitor cells is a key aspect of disease pathogenesis. Several disease-emergent cell types identified in IPF (including KRT5-/KRT17+ aberrant basaloid cells) are abundant in areas of metaplastic epithelial remodeling and active fibrosis, but their role in IPF pathogenesis remains uncertain. Interrogating our single cell transcriptomic data, we identified significant enrichment of gene expression programs regulated by the hypoxia-inducible factor (HIF) family of transcription factors in KRT5-/KRT17+ aberrant basaloid cells. Our preliminary data using genetic and small-molecule based HIF2-targeting suggest that HIF2 inhibition specifically can attenuate experimental lung fibrosis and enhance alveolar repair and regeneration in recurrent injury. Additional studies using mouse and human derived alveolar organoid models demonstrate that HIF2- inhibition enhanced AT2 differentiation and suppressed the emergence of aberrant intermediates similar to disease-emergent cell states identified from IPF patients. Further, HIF2-biased activation in primary human organoids suppressed the TCA cycle, de novo fatty-acid biosynthesis, and promoted the emergence of aberrant intermediate markers. This leads us to hypothesize that HIF2 activation from chronic injury to the distal lung epithelium prevents AT2 cell regeneration from airway progenitors through epigenetic and metabolic modulation of key AT2-requisite biosynthetic functions. We will test this hypothesis by 1) determining how HIF2-activity modulates cellular fate and epigenetic programs during alveolar repair, and 2) delineating the metabolic processes underlying HIF2 suppression of AT2 cell differentiation in the distal lung. These studies will provide essential mechanistic insights in both murine and IPF patient-derived human models into the role of HIF2 in alveolar epithelial remodeling, how its modulation affects adaptive repair, and establishes foundational pre-clinical data for targeting HIF2 as a novel therapeutic strategy for IPF. The highly experienced mentorship team assembled, which includes both physician and basic scientists as well as external advisors, collectively brings expertise in lung epithelial biology, genome regulation, and molecular metabolism which is ideally suited to support my training and career growth as I develop my independent research program.
