Tspan14 expression and function in cardiovascular disease

Tspan14在心血管疾病中的表达和功能

• 批准号: 10656419
• 负责人: Vivian Lee-Kim
• 金额: $ 9.94万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10656419
• 关键词: Adaptor Signaling Protein; Address; Advisory Committees; Affect; Alleles; Animal Model; Apoptosis; Architecture; Basement membrane; Binding; Binding Sites; Bioinformatics; Biological; Biological Process; Biology; Blood Vessels; CD36 gene; Cardiovascular Diseases; Cell membrane; Cell model; Cells; Cholesterol; Chromatin; Chromosomes; Committee Members; Complement; Complex; Coronary Arteriosclerosis; Coronary heart disease; DNA; Data; Dedications; Development; Diabetes Mellitus; Disease; Endothelial Cells; Endothelium; Enhancers; Extracellular Matrix; Fostering; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genetic Predisposition to Disease; Genetic Variation; Grant; Growth; Hematological Disease; Heritability; Human; Hyperlipidemia; Hypertension; Immune; Introns; Laboratories; Lead; Macrophage; Maps; Measures; Mediating; Membrane; Membrane Microdomains; Mentors; Mesenchymal; Minor; Modeling; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathway interactions; Peptide Hydrolases; Phase; Population Genetics; Proteins; Receptor Activation; Regulation; Regulator Genes; Regulatory Element; Research; Research Personnel; Risk Factors; Role; Scientist; Signal Transduction; Supervision; Techniques; Testing; Tissues; Training; Untranslated RNA; Variant; Vascular Diseases; Vascular Endothelial Cell; Writing; Zebrafish; activation-induced cytidine deaminase; causal variant; cell type; differential expression; disorder risk; effective therapy; epigenetic regulation; epigenomic profiling; epigenomics; genetic approach; genome editing; genome wide association study; genomic locus; in vivo; insight; model organism; monocyte; mortality; new therapeutic target; notch protein; novel; novel strategies; prime editing; programs; protective effect; protein function; protein transport; response; risk variant; skills; success; trafficking; transcription factor; transcriptome sequencing; transcriptomics; transdifferentiation

PROJECT SUMMARY/ABSTRACT Genetic predisposition is a significant risk factor for coronary artery disease (CAD), the leading cause of mortality. Most CAD risk variants identified in genome-wide association studies (GWAS) are in noncoding DNA, which poses a major challenge in identifying the target genes in the disease-critical cell types. Using the Activity-by-Contact Model to predict cell type-specific gene-enhancer pairs, we identified cis-regulatory elements in the chromosome 10q23 locus harboring multiple CAD-risk variants. Our preliminary studies show that these enhancers in the 10q23 locus regulate tetraspanin 14 (TSPAN14) gene expression, specifically in vascular endothelial cells (ECs) and monocytes. We have established strong population genetics evidence that higher TSPAN14 expression reduces CAD risk and there is a consistent protective effect for the minor alleles at the lead variants. TSPAN14 is an adaptor protein that aids in trafficking proteins like ADAM10, a Notch receptor activator, to the plasma membrane. The role of Notch pathway activation imparted by this TSPAN14- ADAM10 interaction in CAD pathogenesis has not been explored. In addition, we performed RNA-seq and identified differentially expressed genes in TSPAN14-deficient cells that will help discover Notch-independent TSPAN14 functions. These findings provide a premise for the central hypothesis that the genetic regulation of TSPAN14 by variations in the 10q23 enhancer sequences affects CAD pathogenesis through Notch- dependent and -independent mechanisms in vascular ECs and monocytes. In Aim 1, Dr. Lee-Kim will determine the cell type-specific effect of 10q23 enhancer sequence variations on TSPAN14 expression regulation. In Aim 2, she will determine the Notch-dependent effects of TSPAN14 expression in vascular and immune cells. In Aim 3, she will characterize the Notch-independent TSPAN14 functions in vascular and immune cells. The results from these studies will functionally validate the gene target for noncoding variants associated with CAD-risk in the disease-relevant cell types and elucidate how TSPAN14 functions in CAD pathogenesis. These studies will be conducted under the supervision of mentors, Dr. Rajat Gupta and Dr. Stephen Blacklow, and an advisory committee dedicated to Dr. Lee-Kim’s success. With additional support from the MOSAIC UE5 awardee sponsored professional development opportunities, continued training in the K99 phase will prepare Dr. Lee-Kim for successful transition to independence.

项目总结/文摘