Molecular regulation of cell fate and progenitor function in the distal human respiratory airways

PROJECT SUMMARY/ABSTRACT
This proposal describes a five-year training plan for the development of an independent research career focused
on the role of the distal airway epithelium in human lung injury and regeneration. Specifically, the applicant strives
to understand the regulation of a novel human specific secretory population called respiratory airway secretory
cells (RASCs), which can act as progenitors for alveolar type 2 (AT2) cells, and understand how this population
is altered in Chronic Obstructive Pulmonary Disease (COPD). The applicant is in her final year of Pulmonary and
Critical Care fellowship at the Hospital of the University of Pennsylvania with previous PhD training in cellular
and molecular biology with a focus on cell fate regulation. The goals of this award are to refine and develop skills
that will be necessary for a successful career as an independent investigator including expertise in epigenomics,
mammalian gene editing, and advanced bioinformatic analysis. The mentor for this award is Dr. Edward
Morrisey, an internationally renowned expert in lung regeneration and repair with an outstanding and expansive
training record. Furthermore, an advisory committee of complementary and diverse scientists has been
assembled to provide breadth and depth to the training plan. The applicant will benefit from the unparalleled
mentoring, resources and scientific community at the University of Pennsylvania and the unreserved support of
her institution.
The aims of this proposal are focused on expanding our knowledge of an understudied region of the human
lung, the respiratory bronchioles. Respiratory bronchioles are absent in mouse and hence their role in lung injury,
regeneration and repair is essentially unknown and often over-looked. Recent data demonstrate that respiratory
bronchioles are a site of injury in COPD, highlighting the need to understand the molecular regulation and
function of cell populations within this niche. This project will examine the regulation of a novel cell type recently
identified in the human respiratory bronchioles, RASCs. RASCs can serve as progenitors for AT2 cells, and are
transcriptionally altered in COPD, suggesting that their function could be altered in, and contribute to, the
pathogenesis of this highly prevalent disease. This highlights the scientific need to investigate this cell type and
its response to injury. Successful completion of these proposed studies will address the central hypothesis that
the cell fate and progenitor function of RASCs is regulated through a combination of Notch signaling and the
transcription factor SOX4, and that this progenitor function is altered in COPD. This will be accomplished through
multiple techniques including human embryonic stem cell modeling, next-generation sequencing, and advanced
epigenetic analysis of primary human lung tissue. These studies will provide significant insight into a novel lung
progenitor cell and have a high potential for therapeutic impact in COPD and lung regeneration more broadly.

Grant Number: 5K08HL163398-04
NIH Institute/Center: NIH
Principal Investigator: Maria Basil