Cell-cell and cell-matrix interactions driving progressive fibrosis in interstitial lung diseases
Active Cooperative Agreement Awarded Last action
- Award ID
- U01HL175451
- Recipient
-
University Of California, LOS Angeles UEI RN64EPNH8JC6
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $3,219,306
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 43% complete
- Place of performance
- Los Angeles, CA 90095, USA
Award details come from USAspending.gov.
Description
- Abstract
- Interstitial lung diseases (ILD) are a large group of lung diseases that are characterized by chronic, progressive pulmonary fibrosis. We hypothesize that in all ilds the progressive fibrosis is driven by ongoing injury/stress in the airway epithelial cells that set up crosstalk with their neighboring mesenchymal cells resulting in a chronic wound healing process that alters the matrix and changes the cellular niche. The goal of the proposed research is to address how interactions between the epithelial, mesenchymal and matrix compartments drive progression of fibrosis in all forms of ILD. We are proposing to study these interactions between the epithelial, mesenchymal and matrix compartments, which is now feasible with spatial transcriptomics, single cell secretion protein analysis, and small region proteomics. Most studies have looked at end stage disease and fibrotic lesions where most of the epithelial cells are lost and consequently the initiating and propagating factors are not well understood. We propose to study interstitial lung abnormality (ILA) lesions, which represent very early ILD lesions, early stage ILD lesions when patients start to become symptomatic, and late stage ILD regions that still contain epithelial cells so we can study their interactions with mesenchymal cells and matrix. To test our hypothesis, we have developed a 3D scaffolded lung cell CO-culture model system with progressive fibrosis that closely models these cellular compartments in ILD tissue. We propose the following aims: aim 1: to understand epithelial-mesenchymal interactions in the airway that drive fibrosis using spatial transcriptomics. We will use our biobank of ILD and ILA samples and prospectively collect ILD and ILA patient samples to profile the airway epithelium and underlying fibroblasts from bronchioles to distal airspaces with spatial small region transcriptomics (geomx) and single cell spatial genome-wide transcriptomics (stereoseq). Aim 2: to understand epithelial, mesenchymal and matrix interactions in the airway that drive fibrosis. Aim 2A: we will use the secretory-single cell profiling (SEC-SEQ) technology to capture single airway epithelial cells, from fresh ILA and ILD tissue and trap the secretions from each cell to identify paracrine factors. Aim 2B: we will use nanoscale small region proteomics to identify proteins in the adjacent epithelial, mesenchymal and basement membrane matrix compartments from ILA and ILD samples. Aim 3: to identify mechanisms by which persistent airway injury induces progressive fibrosis by using cell CO- culture models of ipsc derived AT2 cells with specific mutations associated with familial IPF, in conjunction with primary healthy or IPF lung fibroblasts. These powerful reductionist models allow the study of specific epithelial- mesenchymal-matrix interactions that drive progressive fibrosis. We have assembled a team with expertise in spatial transcriptomics and ilds (gomperts), novel bioinformatics pipelines and integration of genomics data (plath), regional small-scale proteomics in ilds (clair), ipsc-derived AT2 disease modeling and ilds (kotton) and bioengineered models of ILD (gomperts).
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $779,780 | |
| Amendment | $794,976 | |
| Amendment | $0 | |
| Amendment | $822,275 | |
| Original award | $822,275 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Battelle Memorial Institute | $242,733 | |
| Trustees Of Boston University | $154,410 |
Quick answers
Who received award U01HL175451?
U01HL175451 was awarded to University Of California, LOS Angeles by National Heart Lung and Blood Institute (National Institutes of Health) on September 1, 2024.
How much is award U01HL175451 worth?
$3,219,306 has been obligated on U01HL175451.
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