Spatial heterogeneity in PIK3CA-mutated lymphatic malformations
Ended Project Grant Awarded Last action
- Award ID
- F32HL172607
- Recipient
-
Seattle Children's Hospital UEI SZ32VTCXM799
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $189,750
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date
- Place of performance
- Washington, USA
Award details come from USAspending.gov.
Description
- Abstract
- Lymphatic malformations (LM) are a common vascular malformation of the head and neck in children, affecting 1-in-4000 live births. LM of the head and neck can be disfiguring and cause life-threatening dysfunction, including airway obstruction and impaired swallowing and speech. LM are caused by defective morphogenesis of lymphatic vessels and surrounding tissue overgrowth due to post-zygotic activating mutations in the oncogene PIK3CA. Interestingly, less than 10% of cells in LM are mutant. Data on how such a small number of mutant cells produce bulky, complex LM are lacking, but localized, intralesional paracrine signaling must play a role. The experiments proposed here aim to elucidate LM pathophysiology using a combination of spatial transcriptomics and in situ single cell genotyping. We will use nanostring to obtain high-throughput spatial analysis of RNA and protein expression data for different cell types and regions of interest in LM tissue. Although we expect to find evidence of PI3K-AKT pathway hyperactivation in both lymphatic endothelial cells (lecs) and LEC-adjacent cells, we hypothesize that gene expression programs will vary based on LEC proximity. We also propose the use of star-fish (specific-to-allele PCR-fish) in situ genotyping to define the mutation status on a single cell level in the context of LM architecture. We hypothesize that while lecs will represent the main class of mutant cells, there will be non-lecs containing PIK3CA mutations, and mutant cell distribution will correlate with regions that demonstrate pathway hyperactivation. Understanding the spatial expression programs and genetic heterogeneity in LM will inform the molecular impact of a single activated oncogene on LM formation and persistence, thus guiding further development and utilization of targeted therapies for these and other vascular malformations. Knowledge from this investigation has broad implications for understanding other mosaic disorders and tumor heterogeneity. The proposed project will be completed under the mentorship of DR. James bennett and DR. Jonathan perkins, as part of a structured research training program that includes formal coursework in genetics, statistics, and bioethics and training in grant writing, manuscript preparation, and research communication.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$0 | |
| Amendment | $4,170 | |
| Amendment | $61,860 | |
| Amendment | $61,860 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Original award | $61,860 |
Quick answers
Who received award F32HL172607?
F32HL172607 was awarded to Seattle Children's Hospital by National Heart Lung and Blood Institute (National Institutes of Health) on May 19, 2024.
How much is award F32HL172607 worth?
$189,750 has been obligated on F32HL172607.
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