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Principal Investigator: Chikage Noishiki
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $86,488
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Varicose veins (VV), which affects approximately 23% of adults in the USA are non-lethal however, it negatively
impacts the quality of life in many patients due to its debilitating symptoms. With limited methods for prevention
and early treatments for VV, there is an unmet need to understand the mechanisms of VVs.
VV pathogenesis is multifactorial and is a combination of epigenetic and genetic factors. In addition,
hemodynamics and inflammation play an important role in venous pathology. Vein wall dilation occurs
concurrently or as a consequence of the venous hypertension and inflammation, further exacerbating the venous
reflux. These changes results in the overexpression of matrix metalloproteinases (MMPs), which causes
degradation of the extracellular matrix proteins, thereby further affecting the structural integrity of the vein wall.
This effect is due to changes in the endothelium (ECs) and smooth muscle cells (SMCs) is the alterations in
cross talk which plays an important role in venous constriction. Alterations in venous tone also contribute to the
development of VV.
Our group identified 30 independent genetic variants associated with VV in a previous genome-wide association
study (GWAS). In complex disease traits, the disease-associated loci may be in non-coding regions even if they
may be responsible for gene expression regulation. It is difficult to know in which cell types or physiological
contexts this regulation occurs. Thus, candidate genes require validation to establish causality. One way of doing
this is with single-cell genomic assays. In our study, we propose to elucidate the molecular mechanisms behind
the development of varicose veins by leveraging the recent advances in single-cell sequencing technologies. By
using single cell RNA-seq, we propose to examine the transcriptomic changes at the single cell level in varicose
veins. Moreover, we propose to decipher the key regulators effecting the different components of the varicose
vein and their effects on ECSMC crosstalk (Aim 1).
Due to limited access to ECs and SMCs from patients (given that the isolation and long-term culture of vascular
cells from patient’s blood is an extremely difficult task), the mechanisms underlying vascular dysfunction in
varicose veins remain largely unknown. As part of Aim 2, we will utilize the induced pluripotent stem cell
technology to recapitulate the disease phenotype of varicose veins in vitro.
Terms: <21+ years old><Adult><Adult Human><Affect><Assay><Bioassay><Biological Assay><Biology><Biomedical Research><Blood><Blood Reticuloendothelial System><Blood Vessels><Body Tissues><Candidate Disease Gene><Candidate Gene><Cardiac Surgery><Cardiac Surgery procedures><Causality><Cell Body><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cells><Clinic><Complex><Data><Development><Digestion><Disease><Disorder><Drug Screening><Early treatment><Endothelium><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Extracellular Matrix Degradation><Extracellular Matrix Proteins><Functional RNA><GWA study><GWAS><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene variant><Genetic><Genome><Heart Surgical Procedures><Hypertension><Impairment><In Vitro><Inflammation><Investigators><Leiomyocyte><MMPs><Matrix Metalloproteinases><Methods><Modeling><Molecular><Myography><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Operative Procedures><Operative Surgical Procedures><Paracrine Communication><Paracrine Signaling><Pathogenesis><Pathology><Patients><Phenotype><Physiologic><Physiological><Play><Prevention><Proteins><QOL><Quality of life><Reflux><Regulation><Research Personnel><Researchers><Resolution><Role><Sample Size><Single cell seq><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Somatic Cell><Structural defect><Structural malformation><Surgical><Surgical Interventions><Surgical Procedure><Technology><Tissues><Untranslated RNA><Validation><Varices><Varicose Veins><Varicosity><Vascular Diseases><Vascular Disorder><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vein graft><Veins><Venous><Venous Blood Pressure><Venous Pressure><Venous Pressure level><adulthood><allele variant><allelic variant><bio-informatics pipeline><bioinformatics pipeline><blood vessel disorder><candidate validation><causation><cell type><compression therapy><constriction><debilitating symptom><develop therapy><developmental><disease causation><disease model><disease phenotype><disease-in-a-dish><disorder model><early therapy><epigenetically><epigenome profiling><epigenomic profiling><gain of function><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><heart surgery><hemodynamics><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><iPS><iPSC><iPSC technology><iPSCs><improved><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cell technology><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><insight><intercellular communication><intervention development><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><noncoding><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><overexpress><overexpression><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><pressure><progenitor cell model><progenitor model><recruit><resolutions><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell genomics><single cell next generation sequencing><single cell sequencing><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><structural abnormalities><structural anomalies><surgery><therapy development><trait><transcriptome profiling><transcriptomic profiling><transcriptomics><treatment development><validations><vascular><vascular dysfunction><vasculopathy><whole genome association analysis><whole genome association studies><whole genome association study>