A5101663004- Renin-Angiotensin System Studies
- Bioinformatics and Genomic Networks
- Cancer-related gene regulation
- Hormonal Regulation and Hypertension
- Genetic Associations and Epidemiology
- Gene expression and cancer classification
- Biomedical Text Mining and Ontologies
- Renal and related cancers
- Cardiac Fibrosis and Remodeling
- Birth, Development, and Health
- Receptor Mechanisms and Signaling
- Genetic and Kidney Cyst Diseases
- Sodium Intake and Health
- Atherosclerosis and Cardiovascular Diseases
- Genetic Mapping and Diversity in Plants and Animals
- Metabolomics and Mass Spectrometry Studies
- Cytokine Signaling Pathways and Interactions
- Molecular Biology Techniques and Applications
- Chronic Kidney Disease and Diabetes
- Epigenetics and DNA Methylation
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- NF-κB Signaling Pathways
- Media Studies and Communication
- RNA regulation and disease
- Genetic Syndromes and Imprinting
Medical College of Wisconsin
2012-2022
Brigham and Women's Hospital
2015
Harvard University
2015
Minneapolis Heart Institute Foundation
2015
University of Minnesota
2015
University of Wisconsin–Milwaukee
2015
Emory University
2012
Center for Human Genetics
2010-2012
Tel Aviv Sourasky Medical Center
2002
Tel Aviv University
2002
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark diabetic kidney disease and associated with an increased risk for end-stage renal cardiovascular events. To gain insight into pathophysiological mechanisms underlying we conducted meta-analyses genome-wide association studies independent replication up to 5,825 individuals European ancestry diabetes 46,061 without diabetes, followed by functional studies. Known associations variants CUBN, encoding cubilin, urinary...
Formed in late 1999, the Rat Genome Database (RGD, https://rgd.mcw.edu) will be 20 2020, Year of Rat. Because laboratory rat, Rattus norvegicus, has been used as a model for complex human diseases such cardiovascular disease, diabetes, cancer, neurological disorders and arthritis, among others, >150 years, RGD always disease-focused committed to providing data tools researchers doing comparative genomics translational studies. At its inception, before sequencing rat genome, started with only...
Genome-wide association studies (GWAS) are useful for nominating candidate genes, but typically unable to establish disease causality or differentiate between the effects of variants in linkage disequilibrium (LD). Additionally, some GWAS loci might contain multiple causative genes that contribute overall susceptibility at a single locus. However, majority current lack statistical power test whether underlie same locus, prompting us adopt an alternative approach testing empirically. We used...
This study reports the consequences of knocking out NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 4 ( Nox4 ) on development hypertension and kidney injury in Dahl salt-sensitive (SS) rat. Zinc finger nuclease injection single-cell SS embryos was used to create an 8 base-pair frame-shift deletion , resulting a loss ≈68 kDa band Western blot analysis renal cortical tissue knock rat (SS Nox4−/− rats. rats exhibited significant reduction salt-induced compared with after 21 days...
Significance Zinc-finger nuclease (ZFN)-mediated mutagenesis has now enabled researchers to manipulate specific genes test their function in animal models other than mice. Applying ZFNs rats, we can the role of human genome-wide association studies (GWAS)-nominated for hypertension a well-characterized hypertensive rat model, Dahl salt-sensitive rat. This study provides first functional evidence that GWAS-nominated gene Plekha7 plays an essential blood pressure regulation and cardiovascular...
While GWAS have been successful in providing variant-to-trait associations for human complex diseases, functional dissection of the discovered loci has lagged behind. Here, we describe a variant-to-gene (V2G) mapping effort Alzheimer's disease (AD) to implicate causal variants and effector genes from most recent AD meta-analyses (101 loci). We leveraged our genomics datasets comprising high-resolution promoter Capture C, ATAC-seq, RNA-seq brain-relevant cell types fine-map variants,...
Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case SH2B adaptor protein 3 (SH2B3), which a negative regulator of multiple cytokine signaling pathways and associated with increased risk myocardial infarction (MI), its role in post-MI inflammation fibrosis completely unknown.Using an experimental model MI (left anterior descending artery occlusion/reperfusion injury)...
To assess the role of anti-heart antibodies (AHA) in postpericardiotomy syndrome (PPS) and timing their appearance relation to initial manifestations PPS.Twenty patients who were scheduled undergo elective coronary artery bypass grafting (CABG) enrolled a prospective, longitudinal pilot study.Serum was sampled for AHA on day prior surgery at regular intervalsfollowing all patients. In those developed PPS, serum determined that typical clinical PPS appeared intervals following onset PPS.All...
Previous studies have identified multiple blood pressure and renal disease quantitative trait loci located on rat chromosome 12. In the present study, we narrowed using a series of overlapping Dahl salt-sensitive/Mcwi (SS)-12 Brown Norway (BN) congenic lines. We found that transferring 6.1 Mb SS 12 (13.4-19.5 Mb) onto consomic SS-12BN background significantly elevated 1% NaCl (146±6 versus 127±1 mm Hg; P<0.001) 8% diets (178±7 144±2 P<0.001). Compared with consomic, these animals also had...
Abstract Model organism research is essential for discovering the mechanisms of human diseases by defining biologically meaningful gene to disease relationships. The Rat Genome Database (RGD, ( https://rgd.mcw.edu )) a cross-species knowledgebase and premier online resource rat genetic physiologic data. This rich enhanced inclusion integration comparative data mouse, as well other models including chinchilla, dog, bonobo, pig, 13-lined ground squirrel, green monkey, naked mole-rat....
Human data and animal models of autosomal recessive polycystic kidney disease (ARPKD) suggest that genetic factors modulate the onset severity disease. We report here for first time ARPKD susceptibility is attenuated by introgressing mutated Pkhd1 allele from (PCK) rat onto FHH (Fawn-Hooded Hypertensive) background. Compared with PCK, FHH.Pkhd1 strain had significantly decreased renal cyst formation coincided a threefold reduction in mean weights. Further analysis revealed FHH. protected...
A 3.7-Mb region of rat chromosome 13 (45.2-49.0 Mb) affects blood pressure (BP) in females only, indicating the presence sex-specific BP loci close proximity to Renin locus. In present study, we used a series Dahl salt-sensitive/Mcwi-13 Brown Norway congenic strains further resolve within this region. We identified 3 affecting female rats which 2 smaller (line9BP3 and line9BP4) were functionally characterized by sequence expression analysis. Compared with SS (SS/HsdMcwiCrl), 591-kb BN...
Abstract Biological interpretation of a large amount gene or protein data is complex. Ontology analysis tools are imperative in finding functional similarities through overrepresentation enrichment terms associated with the input lists. However, most limited by their ability to do ontology-specific and species-limited analyses. Furthermore, some not updated frequently recent information from databases, thus giving users inaccurate, outdated uninformative data. Here, we present MOET...
Renin was the first blood pressure (BP) quantitative trait locus mapped by linkage analysis in rat. Subsequent BP and congenic studies capturing different portions of renin region have returned conflicting results, suggesting that multiple interdependent loci may be residing chromosome 13 includes Renin. We used SS-13(BN) strains to map 2 (chr13: 45.2-49.0 Mb). identified a 1.1-Mb protective Brown Norway around 46.1-47.2 Mb) significantly decreased 32 mm Hg. The offset an adjacent...
Previously, we found that transferring 6.1 Mb of salt-sensitive (SS) chromosome 12 (13.4–19.5 Mb) onto the consomic SS-12 BN background significantly elevated mean arterial pressure in response to an 8% NaCl diet (178±7 versus 144±2 mm Hg; P <0.001). Using congenic mapping, have now narrowed blood locus by 86% from a 6.1-Mb region containing 133 genes 830-kb (chr12:14.36–15.19 with 14 genes. Compared consomic, was associated ∆+15 Hg ( <0.01) increase pressure, which coincided...
Rf-3, a quantitative trait locus (QTL) on rat chromosome 3, affects the development of CKD in Fawn-Hooded Hypertensive (FHH) rats. This QTL spans 110 Mb and approximately 1400 genes; therefore, narrowing position this is necessary to elucidate potential candidate genes. Here, we used congenic models comparative genomics refine Rf-3 region. We generated lines carrying smaller intervals (subcongenics) region these reduce by 94% (to 7.1 Mb). identify for both nephropathy albuminuria syntenic...
The classic renin-angiotensin system is partly responsible for controlling aldosterone secretion from the adrenal cortex via peptide angiotensin II (ANG II). In addition, there a local adrenocortical that may be involved in control of synthesis zona glomerulosa (ZG). To characterize long-term steroidogenesis, we utilized glands renin knockout (KO) rats and compared steroidogenesis vitro steroidogenic enzyme expression to wild-type (WT) controls (Dahl S rat). Adrenal capsules (ZG; production)...
The combined transfer of two renal function quantitative trait loci (QTLs), Rf-1 (rat chromosome 1) and Rf-4 14), from the Fawn-hooded hypertensive rat onto August Copenhagen Irish genetic background significantly increases proteinuria demonstrates an interaction between these QTLs. Because original congenic region is 61.9 Mbp, it necessary to reduce this interval feasibly search for variants responsible susceptibility in region. Here, we generated a minimal line (Rf-1a+4_a) identify 4.1-Mb...
Rats have been used as research models in biomedical for over 150 years. These disease arise from naturally occurring mutations, selective breeding and, more recently, genome manipulation. Through the innovation of genome-editing technologies, genome-modified rats provide precision by disrupting or complementing targeted genes. To facilitate use these data produced rat models, Rat Genome Database (RGD) organizes strains and annotates with qualitative phenotype terms well quantitative...
We previously isolated a 6.1-Mb region of SS/Mcwi (Dahl salt-sensitive) rat chromosome 12 (13.4-19.5 Mb) that significantly elevated blood pressure (BP) (Δ+34 mmHg, P < 0.001) compared with the SS-12(BN) consomic control. In present study, we examined role vascular dysfunction and remodeling in hypertension risk associated locus on by reducing dietary salt, which lowered BP levels so there were no substantial differences between strains. Consequently, any observed vasculature considered...
Hypertension (HTN) is a complex disease influenced by heritable genetic elements and environmental interactions. Dietary salt among the most influential modifiable factors contributing to increased blood pressure (BP). It well established that men women develop BP impairment in different patterns recent emphasis has been placed on identifying mechanisms leading differences observed between sexes HTN development. The current work reported here builds an extensive mapping experiment sought...