Program to block age-related pulmonary fibrosis and restore lung regeneration

About This Grant

ABSTRACT In the US alone ~200,000 patients present yearly with Idiopathic Pulmonary Fibrosis (IPF), a relentlessly progressive disorder with average survival of 3-5 years that is strongly linked to aging. No FDA approved drug improves lung function or well-being, underscoring the medical need for new therapeutics. The central premise of this research program is that development and progression of metaplastic alveolar epithelial cells are the principal drivers of disease and poor outcome in IPF. In addition to a body of prior work on IPF risk, two recent discoveries by our group support this claim and are the basis for this R35 application: (1) Human alveolar type II cells (AT2s) are much more plastic than previously known and capable of transdifferentiation not only to normal alveolar type 1 cells (AT1s) but also pro-fibrotic alveolar basaloid/basal cells and lining cells of respiratory bronchioles. Spatial transcriptomic analysis of IPF respiratory bronchioles suggests they expand and create basal cell-like microcystic structures characteristic of IPF. Accumulation of these microcysts and alveolar basal cells both correlate with poor outcome for IPF patients. These findings provide a well-developed alternative to the long-held belief, termed bronchiolization, that accumulation of alveolar basal and other airway cells in IPF derive from airway cells. (2) Transdifferentiation of human AT2s to basaloid/basal cells is strongly age-dependent, tracking with the well-known advanced age of IPF onset. A central hypothesis of the program is that epigenetic and transcriptional regulators of AT2 cells operate to bias AT2 differentiation under injury/stress conditions with age toward basal cells at the expense of AT1 renewal. The core regulation of basaloid/basal cell transdifferentiation has two elements: the first is age-dependent epigenetic accessibility of basal cell gene promoters. We will pursue preliminary data that a key driver of the aged epigenetic landscape is AT2 cells expressing inflammatory mediators. Once accessible, the second element is assembly of transcriptional drivers of Krt5 mRNA expression including tp63 and Hif1a. Assembly of these drivers on the Krt5 gene also inhibits AT1 Rage transcription leading to marked age-dependent basal cell bias and impaired lung regeneration. We believe a more mechanistic and accurate understanding of IPF epithelial cytopathology will advance the fibrosis field by providing a better rationale for new therapeutic leads. Indeed, as part of the R35 mechanism, based on our recent findings, we will undertake a HTS small molecule screen using iPSC- derived iAT2 cells to identify compounds that reverse the basaloid/basal state.