Defining Cell Populations and Cell Type-Specific Transcriptional Dysregulation in Pediatric Coarctation of the Aorta
Abstract
The aorta is the largest blood vessel in the body and is responsible for delivering the blood that has been ejected from the heart to the body’s organs. Coarctation of the aorta (CoA) is a common form of congenital heart disease, which is a Peer Reviewed Medical Research Program (PRMRP) Topic Area. CoA is defined by an abnormal narrowing of the aorta that is due to abnormal in utero development. After birth, CoA obstructs blood flow from the aorta to the rest of the body, resulting in organ injury including heart failure. Currently, infants with severe CoA require invasive cardiac surgery. In such operations, the area of coarctation is resected and removed from the body along with portions of the adjacent aortic tissues that do not have CoA. Surgery has significant costs and associated risks including death and organ injury. Even when surgery is uncomplicated and repair is excellent, many patients remain at long-term risk to develop other cardiovascular problems including increased blood pressure and early-onset coronary artery disease. Therefore, surgery does not fundamentally cure CoA. There are currently no medications to prevent CoA development, cure CoA postnatally, or specifically prevent or treat the long-term associated cardiovascular diseases. In order to develop such medical treatments, which are urgently needed, the precise disease mechanisms that cause CoA must be more clearly understood. The objective of this proposal is to precisely define the types of cells that are abnormally located in the diseased aortic tissues of neonates with CoA and determine how specific types of cells are abnormally functioning. We will pursue this objective using a cutting-edge technique called single-cell RNA sequencing (sc-RNAseq). In sc-RNAseq, every cell in a tissue is analyzed individually for how its genes are being expressed. The aorta has a mixture of cells including endothelial cells, smooth muscle cells, and others. From the data that is generated by scRNA-seq, in a single test each individual cell can be labeled according to what type of cell it is. This allows for a complete understanding of the types of cells and their relative amounts, as well as identifying the cells that are not normally present. The data can also be used to select the populations of specific types of cells and then perform a cell type-specific analysis of gene expression. Our central hypothesis is that CoA tissues contain distinctive cell populations and that comprehensive analysis of specific types of cells will provide a precise understanding of cell abnormalities that are driving the disease. We propose to study the blood vessels that are removed surgically in infants with CoA in the course of routine clinical care. We have a fully developed infrastructure for the recruitment of study participants and collection of aortic biospecimens at our high-volume pediatric cardiac center. For each participant, we will perform sc-RNAseq of several tissue pieces, including the area of CoA and the adjacent blood vessels. These include the adjacent parts of the aorta that do not have CoA. In our first aim, we will define the types of cells that are located in each piece of resected tissue, hypothesizing that the CoA tissue will contain distinct cell population(s) and different amounts and proportions of cell types compared with the adjacent aortic tissues that do not have CoA. In our second aim, we will select specific types of cells in order to perform a cell type-specific analysis of gene expression. For each selected cell type, we will compare gene expression levels between different aortic tissue segments. We expect to identify genes that have abnormal expression levels in CoA and understand which specific types of cells display the abnormalities. This research is innovative because it will utilize sc-RNAseq for the first time in CoA. This research is conceptually innovative because it seeks to overcome the critical lack of understanding of the disease pro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310009
Entities
People
- Benjamin Landis
Organizations
- Indiana University
- United States Army