Research

LRRC Funded Research

The LRRC provides funding to our Principal Investigators and their collaborators through two mechanisms – parent U01 grants and the competitive Collaborative Research and Tool Validation (CReATV) projects.

Individual U01 Awards:

Cincinnati Children’s Hospital – Oregon Health and Science University
Airway Progenitor Cell Proliferation and Differentiation During Lung Repair

Jeffrey A. Whitsett, MD (Contact PI)
Cincinnati Children’s Hospital

Philip Streeter, PhD
Oregon Health and Science University

Duke – University of North Carolina Chapel Hill – Cedars Sinai
An Integrated Approach to Airway Epithelial Repair and Regeneration

Brigid L.M. Hogan, PhD (Contact PI)
Duke University

Scott Randell, PhD
University of North Carolina-Chapel Hill

Barry Stripp, PhD
Cedars Sinai

University of California-San Francisco
Epithelial Progenitor Cells in Lung Repair and Regeneration

Harold Chapman, MD (Contact PI)
University of California-San Francisco

Pao-Tien Chuang, MD
University of California-San Francisco

Matthew Krummel, PhD
University of California-San Francisco

University of Pennsylvania
Epigenic Regulation of Lung Progenitor Repair and Regeneration

Ed Morrisey, PhD
University of Pennsylvania

University of Texas-Southwestern – University of Texas-Arlington
Nanoparticle Drug Delivery in Post-Pneumonectomy Compensatory Lung Growth

Connie Hsia, MD (Contact PI)
University of Texas Southwestern

Kytai Nyugen, PhD
University of Texas Arlington

Yale University – University of Michigan
Matrix and Bioreactors for Human Lung Regeneration

Laura Niklason, PhD, MD (Contact PI)
Yale University

Eric Stephen White, MD
University of Michigan

Collaborative Research and Tool Validation (CReATV) Projects:

CReATV 1

Sense and Antisense Erythropoietin Receptor Transcripts and Proteins
Principal Investigator: Connie Hsia, MD – University of Texas Southwestern
Co-Investigators:
Philip Streeter, PhD – Oregon Health & Science University
Orson Moe – University of Texas Southwestern

The goals of this project are to produce novel reagents and validate new concepts for paracrine/autocrine erythropoietin (EPO) signaling through its receptor (EPOR). Specific Aims: 1) generate specific anti-EPOR and anti-ROPE (antisense polypeptide) monoclonal antibodies. 2) Define temporal-spatial expression patterns of sense and antisense EPOR transcripts, and EPOR and ROPE proteins through fetal and postnatal life in mice.

Endodermal Progenitor Cell Reconstitution of the Decellularized Rat Lung
Principal Investigator: Laura Niklason, PhD, MD – Yale University
Co-Investigator:
Paul Gadue, PhD – Children’s Hospital of Pennsylvania (CHOP)

The goals of this project are to investigate the ability of a newly discovered human endodermal stem cell population to differentiate into lung lineage cell types in the decellularized rat lung. The studies will provide a protocol for the generation of functional lung lineage cells from human stem cells in a physiologically relevant decellularized organ. The ability to generate endodermal stem cells from any iPS cell line offers an extremely powerful system to generate patient specific lung tissue; initially engineered for the study of basic biology and disease modeling, this system also holds the potential for future use in cell-based therapies.

Novel Monoclonal Antibodies for Human Lung Progenitor Cells
Principal Investigator: Scott Randell, PhD – University of North Carolina Chapel Hill
Co-Investigators:
Philip Streeter, PhD – Oregon Health & Science University
Jeffrey Whitsett, MD – Cincinnati Children’s Hospital
Brigid Hogan, PhD, FRS – Duke University
Barry Stripp, PhD – Cedars Sinai

The goal of this project is to discover novel monoclonal antibodies (mAbs) useful to sort and test the growth capacity and differentiation potential of primary human tracheobronchial epithelial (hTBE) cell subpopulations. Reactivity will also be analyzed in normal and diseased human lung tissue specimens.

CReATV 2

Antibodies to Human Alveolar Epithelial Progenitor Cells
Principal Investigator: Hal Chapman, MD – University of California at San Francisco
Co-Investigator:
Philip Streeter, PhD – Oregon Health & Science University

The goals of this project are to identify human lung alveolar stem/progenitor cell population(s) that are distinct from small airway basal cells or type II cells and develop monoclonal antibodies to identify (and eventually isolate) these cells.

Assessment of Interconversion and Plasticity of Type I and Type II Pulmonary Alveolar Epithelial Cells
Principal Investigator: Jonathan Epstein, MD – University of Pennsylvania
Co-Investigator:
Brigid Hogan, PhD, FRS – Duke University

The goal of this project is to address a key issue in lung regeneration and repair using novel, state of the art in vivo lineage tracing, combined with novel in vitro 3D cultures. The investigators will address whether and when type I and type II lung alveolar cells can interconvert. It has been shown that Type II cells can make Type I cells but the reverse is not as clear.

Novel Tools for Outcome Assessment in Mouse Lungs
Principal Investigator: Connie Hsia, MD – University of Texas Southwestern
Co-Investigators:
Hal Chapman, MD – University of California at San Francisco

The goal of this project is to develop physiological assays and in vivo imaging techniques to assess function of gas exchange in mouse models to enable and validate human physiology measurements to murine models.

CReATV 3

Optimizing Hydrogel Scaffolds for Bioengineered Human Airway Graft
Principal Investigator: Brigid Hogan, PhD, Duke University
Co-Investigators:
Jennifer West, PhD, Duke University
Scott Randell, PhD UNC-Chapel Hill

The goal of this project is to design and optimize biodegradable hydrogels that mimic extracellular matrix (ECM) functions, delivering specific adhesion peptides, growth factors and signaling molecules. There is a great need for bioengineered human airway segments, and the investigators propose to address this by developing improved scaffolds to support cell growth.

Generation and Analysis of Gene Corrected SFTP Mutations in iPSC lines
Principal Investigator: Edward Morrisey, PhD – University of Pennsylvania
Co-Investigators:
Darrell Kotton, MD – Boston University
Kathleen Stewart – University of Pennsylvania

The goal of this proposal is to formally integrate into the LRRC the in vitro model system of human induced pluripotent stem cells (iPSCs) to enable patient-specific lung disease modeling, drug screening, and tissue engineering. This project brought to the LRRC the expansive lung disease-specific human iPSC bank currently housed at the Boston University Center for Regenerative Medicine and focuses specifically on the clinical translation of this novel stem cell model to advance the study of degenerative lung diseases caused by dysfunction of the alveolar type 2 epithelial cell (AEC2). Specifically the investigators will purify an expandable supply of patient-specific AEC2 with various disease causing mutations in the SFTPC gene, and provide locus-specific gene-editing in these cells to gene-correct SFTPC mutations that lead to AEC2 dysfunction.

Isolation and Characterization of Stromal Cells from Human Lungs
Principal Investigator: Jason Rock, PhD – University of California at San Francisco
Co-Investigators:
Hal Chapman, PhD – University of California at San Francisco

The goal of this project is to use flow markers, staining of OCT embedded lung tissue, and molecular (mRNA analysis) and functional (colony forming assays) characterization will be used characterize the heterogeneity of stromal cells in the distal human lung, both normal and fibrotic.

Epithelium and Epithelial Progenitor Re-seeding of Human Lung Scaffolds
Principal Investigator: Eric White, MD – University of Michigan
Co-Investigators:
Hal Chapman, PhD – University of California at San Francisco

The goal of this project is to develop methodologies to re-seed, decellularized human lung scaffold using a semi-function bioengineered model system. If successful, the subsequent differentiation of re-seeded epithelial cells will be characterized. In parallel experiments, the investigators will address the effect of fibrotic extracellular matrix (ECM) scaffolds on reseeding and differentiation.

Single Cell NexGen RNA Sequencing of Human Lung
Principal Investigator: Jeffrey Whitsett, MD – Cincinnati Children’s Hospital
Co-Investigators:
Barry Stripp, PhD – Cedars Sinai
B. Aronow, S. Potter, Y. Xu – Cincinnati Children’s Hospital

The goal of this project is to use single cell RNA sequencing of cells of the human lung to provide insights into heterogeneity and hierarchies of cells in the lung epithelium and parenchyma. If successful these findings will be necessary in interpreting pathobiology and developing cell, gene and drug based therapies.

CReATV 4

A Novel Platform to Assess Gene Function in Human Airway Basal Cells

Principal Investigators: Edward Morrisey, PhD – University of Pennsylvania and Brigid Hogan, PhD, Duke University
Co-Investigator:  Jonathan Epstein, MD – University of Pennsylvania

The goal of this project is to to build an assay platform that explores gene function in critical human lung cell populations, and use it to screen for important chromatin remodeling factors, including lncRNAs, transcriptional regulators and chromatin modifying factors, in primary human bronchial epithelial (HBE) cells as they self-renew as undifferentiated basal stem cells (BCs) and give rise to secretory and ciliated cell types.

Identification of Cell Lineage Heterogeneity in Human Lungs

Principal Investigator: Hal Chapman, PhD – University of California at San Francisco
Co-Investigators:
Jason Rock, PhD – University of California at San Francisco

Edward Morrisey, PhD – University of Pennsylvania

Scott Randell, PhD UNC-Chapel Hill

The goal of this project is to to build an assay platform that explores gene function in critical human lung cell populations, and use it to screen for important chromatin remodeling factors, including lncRNAs, transcriptional regulators and chromatin modifying factors, in primary human bronchial epithelial (HBE) cells as they self-renew as undifferentiated basal stem cells (BCs) and give rise to secretory and ciliated cell types.