A5055887373- Atherosclerosis and Cardiovascular Diseases
- Immune cells in cancer
- Angiogenesis and VEGF in Cancer
- Adipokines, Inflammation, and Metabolic Diseases
- Lipoproteins and Cardiovascular Health
- Computational Drug Discovery Methods
- Hormonal Regulation and Hypertension
- Bioinformatics and Genomic Networks
- Cardiovascular Disease and Adiposity
- Peroxisome Proliferator-Activated Receptors
- Autophagy in Disease and Therapy
- Cell Adhesion Molecules Research
- Adipose Tissue and Metabolism
- Neuroendocrine regulation and behavior
- Nuclear Receptors and Signaling
- SARS-CoV-2 and COVID-19 Research
- Birth, Development, and Health
- FOXO transcription factor regulation
- Cardiovascular Health and Disease Prevention
- Protease and Inhibitor Mechanisms
- Circadian rhythm and melatonin
- Pancreatic function and diabetes
- Cell Image Analysis Techniques
- Blood Coagulation and Thrombosis Mechanisms
- Epigenetics and DNA Methylation
Brigham and Women's Hospital
2015-2025
Harvard University
2015-2025
Boston University
2008-2023
Dana-Farber/Harvard Cancer Center
2021
Juzo (Germany)
2018
Juntendo University
2015
Massachusetts Institute of Technology
2015
Harvard–MIT Division of Health Sciences and Technology
2015
University of Sassari
2007
University School
2007
Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent risk factor in CKD. We explored the potential impact of on proinflammatory activation macrophages and its underlying mechanisms.We examined vitro effects clinically relevant concentrations responses roles organic anion transporters transporting polypeptides (OATPs). A systems approach, involving unbiased global proteomics,...
Background: Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role in macrophage activation and vein largely unknown, especially through LDLR-independent mechanisms. This study aimed explore novel mechanism disease induced by circulating an...
Cellular heterogeneity of aortic valves complicates the mechanistic evaluation calcification processes in calcific valve disease (CAVD), and animal models are lacking. In this study, we identify a disease-driver population (DDP) within valvular interstitial cells (VICs). Through stepwise single-cell analysis, phenotype-guided omic profiling, network-based characterize DDP fingerprint as CD44highCD29+CD59+CD73+CD45low discover potential key regulators human CAVD. These DDP-VICs demonstrate...
Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits vitro exploration proinflammatory mechanisms and the development novel immune therapies. We hypothesized that study macrophage subpopulations could lead to anti-inflammatory interventions.
Objective— Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested hypothesis that Notch signaling promotes disease. Approach Results— used 2 biotherapeutics Delta-like ligand 4 (Dll4), a ligand: (1) blocking antibody (2) macrophage- or endothelial cell (EC)–targeted small-interfering RNA. Dll4 administration 28 days inhibited lesion development in low-density lipoprotein (LDL)...
Vein graft failure remains a common clinical challenge. We applied systems approach in mouse experiments to discover therapeutic targets for vein failure.Global proteomics and high-dimensional clustering on multiple tissues were used identify potential pathogenic mechanisms. The PPARs (peroxisome proliferator-activated receptors) pathway served as an example substantiate our discovery platform. In vivo with macrophage-targeted PPARα small interfering RNA, or the novel, selective activator...
Abstract The coronavirus disease (COVID-19) pandemic has occurred in Massachusetts multiple waves led by a series of emerging variants. While the evidence linked obesity with severe symptoms COVID-19, effect on susceptibility to SARS-CoV-2 infection remains unclear. Identification intrinsic factors, which increase likelihood exposed individuals succumbing productive could help plan mitigation efforts curb illness. We aim investigate whether obese have higher developing given comparable...
Essential hypertension remains a major risk factor for cardiovascular and cerebrovascular diseases. As complex multifactorial disease, elucidation of susceptibility loci elusive. ATP1A1 Dear are candidate genes 2 closely linked rat chromosome-2 blood pressure quantitative trait loci. Because corresponding human syntenic regions on different chromosomes, investigation (chromosome [chr]-1p21) (chr-4q31.3) facilitates genetic analyses each locus in hypertension. Here we report the association...
Multiple clinical studies show that arterial stiffness, measured as pulse wave velocity (PWV), precedes hypertension and is an independent predictor of end organ diseases including stroke, cardiovascular disease chronic kidney disease. Risk factor for stiffness implicate age, sodium. However, causal mechanisms linking risk to remain be elucidated. Here, we studied the relationship in Na-induced, stroke-prone Dahl salt-sensitive (S) hypertensive rat model, analyzed putative molecular...
Probing the dynamic control features of biological networks represents a new frontier in capturing dysregulated pathways complex diseases. Here, using patient samples obtained from pancreatic islet transplantation program, we constructed tissue-specific gene regulatory network and used centrality (Cc) concept to identify high (HiCc) pathways, which might serve as key pathobiological for Type 2 Diabetes (T2D). We found that HiCc pathway genes were significantly enriched with modest GWAS...
Stroke is the third leading cause of death in United States with high rates morbidity among survivors. The search to fill unequivocal need for new therapeutic approaches would benefit from unbiased proteomic analyses animal models spontaneous stroke prestroke stage. Since brain microvessels play key roles neurovascular coupling, we investigated microvascular proteome changes. Proteomic analysis cerebral cortical (cMVs) was done by tandem mass spectrometry comparing two time points....
Conventional drug screening methods search for a limited number of small molecules that directly interact with the target protein. This process can be slow, cumbersome and has driven need developing new approaches to counter rapidly emerging diseases such as COVID-19. We propose pipeline repurposing combining in silico candidate identification followed by vitro characterization these candidates. first identified gene interest, entry receptor SARS-CoV-2 virus, angiotensin converting enzyme 2...
A priori, a common receptor induced in tumor microvessels, cancer cells and stem-like (CSCs) that is involved angiogenesis, invasiveness, CSC anoikis resistance survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show functional analysis the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports putative paradigm pancreatic ductal adenocarcinoma (PDAC) glioblastoma (GBM) selected for their...
Early-life risk factor exposure increases aortic atherosclerosis and blood pressure in humans animal models; however, limited insight has been gained as to end-organ complications.We investigated the effects of early-life Na (0.23% versus 0.4% NaCl regular rat chow) on vascular disease outcomes using inbred, transgenic [hCETP](25) Dahl salt-sensitive hypertensive model male-predominant coronary atherosclerosis, Tg25. Rather than expected increase heart disease, fetal (< or =2 g per 2-kcal/d...
Arterial stiffness is an independent predictor of cardiovascular outcomes in hypertensive patients including myocardial infarction, fatal stroke, cerebral micro-bleeds which predicts hemorrhage patients, as well progression to hypertension non-hypertensive subjects. The association between arterial and various (coronary heart disease, stroke) remains after adjusting for age, sex, blood pressure, body mass index other known predictors suggesting that stiffness, measured via carotid-femoral...
Short-term preoperative methionine restriction (MetR) is a promising translatable strategy to mitigate surgical injury response. However, its application improve post-interventional vascular remodeling remains underexplored. Here we find that MetR protects from arterial intimal hyperplasia in focal stenosis model and pathologic following vein graft surgery male mice. RNA sequencing reveals enhances browning (thoracic aorta) perivascular adipose tissue (PVAT) induces it venous (caval vein)...
Identification of juvenile protective factors (JPFs) which are altered with age and contribute to adult-onset diseases could identify novel pathways for reversing the effects age, an accepted non-modifiable risk factor diseases. Since endothelial progenitor cells (EPCs) have been observed be in stroke, hypertension hypercholesterolemia, said EPCs candidate JPFs stroke. A priori, if EPC aging plays a 'master-switch JPF-role' stroke pathogenesis, therapy alone should delay stroke-onset. Using...
Aside from abnormal angiogenesis, dual endothelin-1/VEGF signal peptide-activated receptor deficiency ( DEspR −/− ) results in aberrant neuroepithelium and neural tube differentiation, thus elucidating DEspR's role neurogenesis. With the emerging importance of neurogenesis adulthood, we tested hypothesis that nonembryonic-lethal haploinsufficiency +/− perturbs neuronal homeostasis, thereby facilitating aging-associated neurodegeneration. Here show that, male mice only,...
The angiotensin-vasopressin receptor (AVR) responds with equivalent affinities to angiotensin II (ANG II) and vasopressin is coupled adenylate cyclase hence a V2-type receptor. AVR maps the Nalp6 locus overlaps larger Nalp6/PYPAF5 reported be T cell/granulocyte-specific, cytoplasmic-specific proapoptotic protein, thus questioning existence of AVR. Here we confirm, through different experimental modalities, that distinct from based on mRNA protein sizes, subcellular localization,...
Arginine vasopressin (AVP) and angiotensin II (ANG II) are distinct peptide hormones involved in multiple organs modulating renal, cardiovascular, brain functions. They achieve these functions via specific G protein-coupled receptors, respectively. The AVR/NAVR locus encodes two overlapping V2-type isoreceptors: angiotensin-vasopressin receptor (AVR) responding to ANG AVP equivalently, nonangiotensin (NAVR), which binds exclusively. AVR NAVR expressed from a single gene by alternative...