A5009301036- Renal Diseases and Glomerulopathies
- Renal and related cancers
- Chronic Kidney Disease and Diabetes
- Inflammasome and immune disorders
- Genetic and Kidney Cyst Diseases
- Cellular transport and secretion
- SARS-CoV-2 and COVID-19 Research
- Multiple Myeloma Research and Treatments
- Heme Oxygenase-1 and Carbon Monoxide
- COVID-19 Clinical Research Studies
- Retinal Development and Disorders
- IL-33, ST2, and ILC Pathways
- Calcium signaling and nucleotide metabolism
- Lipid Membrane Structure and Behavior
- Acute Kidney Injury Research
- Chronic Lymphocytic Leukemia Research
- Photoreceptor and optogenetics research
- Biomarkers in Disease Mechanisms
- Vascular Malformations and Hemangiomas
- Genomics and Rare Diseases
- Protein Degradation and Inhibitors
- Vasculitis and related conditions
- SARS-CoV-2 detection and testing
- Chronic Myeloid Leukemia Treatments
- AI in cancer detection
University of Calgary
2012-2025
Analysis Group (United States)
2022-2024
Beth Israel Deaconess Medical Center
2018-2022
Harvard University
2018-2022
Johns Hopkins University
2020-2022
Johns Hopkins Medicine
2020
University of Alberta
2004-2010
Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1β and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed processing caspase-1, IL-1β, IL-18 after unilateral ureteral obstruction (UUO) mice, which suggested activation Nlrp3 inflammasome injury. Compared with wild-type Nlrp3−/− mice had less tubular injury, inflammation, fibrosis UUO, associated reduction...
Abstract Tubulointerstitial inflammation and fibrosis are strongly associated with the outcome of chronic kidney disease. We recently demonstrated that NOD-like receptor, pyrin domain containing-3 (NLRP3) contributes to renal inflammation, injury, following unilateral ureteric obstruction in mice. NLRP3 expression tubular epithelial cells (TECs) was found be an important component experimental disease pathogenesis, although biology is unknown. In human mouse primary TECs, increased response...
The non-canonical caspase-4 and canonical NLRP3 inflammasomes are both activated by intracellular lipopolysaccharide (LPS), but the crosstalk between these two pathways remains unclear. Shiga toxin 2 (Stx2)/LPS complex, from pathogenic enterohemorrhagic Escherichia coli, activates caspase-4, gasdermin D (GSDMD), inflammasome in human THP-1 macrophages, not mouse macrophages that lack Stx receptor CD77. Stx2/LPS-mediated IL-1β secretion pyroptosis dependent on mitochondrial reactive oxygen...
Radiographic contrast agents cause acute kidney injury (AKI), yet the underlying pathogenesis is poorly understood. Nod-like receptor pyrin containing 3–deficient (Nlrp3-deficient) mice displayed reduced epithelial cell and inflammation in a model of contrast-induced AKI (CI-AKI). Unexpectedly, directly induced tubular death vitro that was not dependent on Nlrp3. Rather, activated canonical Nlrp3 inflammasome macrophages. Intravital microscopy revealed diatrizoate (DTA) uptake within minutes...
The mechanisms that drive leukocyte recruitment to the kidney are incompletely understood. Dipeptidase-1 (DPEP1) is a major neutrophil adhesion receptor highly expressed on proximal tubular cells and peritubular capillaries of kidney. Renal ischemia reperfusion injury (IRI) induces robust monocyte causes acute (AKI). inflammation AKI phenotype were attenuated in Dpep1-/- mice or pretreated with DPEP1 antagonists, including LSALT peptide, nonenzymatic inhibitor. deficiency inhibition...
The generation of kidney organoids derived from human induced pluripotent stem cells offers various applications such as tissue regeneration, drug screening, and disease modeling. traditional methodology for generating presents challenges, including labor-intensive procedures, limited scalability, batch-to-batch variability in organoid quality. To address these obstacles, we have developed a low-cost readily accessible automated three-dimensional bioprinting platform capable printing nephron...
Significance Specific APOL1 variants are a strong risk factor for human kidney disease. Previous reports examining the intracellular localization of protein in and glomerular podocytes have yielded inconsistent results. Here we demonstrate differential wild-type variant polypeptides, with wild type localizing predominantly to lipid droplets forms endoplasmic reticulum. We further that modulates cytotoxic effects, perturbations increasing droplet polypeptides decrease this cytotoxicity. These...
Abstract Nod-like receptor pyrin domain-containing-3 (NLRP3) has been implicated in the pathogenesis of experimental renal injury, yet its characterization human kidney disease remains largely unexplored. NLRP3 expression was evaluated biopsies, primary tubular cells (HPTC) and correlated to outcomes patients with IgA nephropathy (IgAN). localized tubules normal tissue mitochondria within HPTC by immunohistochemistry immunofluorescence microscopy. Compared control kidneys, gene increased...
The formation and maturation of membrane carriers that transport cargo from the ER to Golgi complex involves sequential action coat protein complexes COPII COPI. Recruitment COPI nascent requires activation ADP-ribosylation factors by a BrefeldinA-sensitive guanine nucleotide exchange factor. Using new antisera GFP-tagged protein, we demonstrate factor GBF1 localized both membranes peripheral puncta, near but separate exit sites. Live cell imaging revealed GFP-GBF1 associates dynamically...
We examined the relative function of two classes guanine nucleotide exchange factors (GEFs) for ADP-ribosylation that regulate recruitment coat proteins on Golgi complex. Complementary overexpression and RNA-based knockdown approaches established GBF1 regulates COPI cis-Golgi compartments, whereas BIGs appear specialized adaptor trans-Golgi. Knockdown and/or did not prevent export VSVGtsO45 from endoplasmic reticulum (ER), but caused its accumulation into peripheral vesiculotubular clusters....
Despite extensive work on ADP-ribosylation factor (Arf) 1 at the Golgi complex, functions of Arf2-5 in secretory pathway, or for that any Arf ER-Golgi intermediate compartment (ERGIC) remain uncharacterized. Here, we examined recruitment fluorescently tagged Arf1, -3, -4, and -5 onto peripheral ERGIC. Live cell imaging detected Arfs puncta also contained Golgi-specific brefeldin A (BFA) resistance (GBF) ERGIC marker p58. Unexpectedly, BFA did not promote corecruitment with GBF1 either...
Significance Statement Despite many known monogenic causes of FSGS, single gene defects explain only 30% cases. In this study, sequencing 662 exomes from families with FSGS and 622 control validated FSGS-causing genes. However, for some genes previously reported as related, they identified a number purported “disease-causing” variants in controls at similar or higher frequencies. They also multiple additional candidate which rare were more common among Network analysis showed that their...
Two variants in the gene encoding apolipoprotein L1 (APOL1) that are highly associated with African ancestry major contributors to large racial disparity rates of human kidney disease. We previously demonstrated recruitment APOL1 risk G1 and G2 from endoplasmic reticulum lipid droplets leads reduced APOL1-mediated cytotoxicity podocytes.We used CRISPR-Cas9 editing induced pluripotent stem cells develop human-derived APOL1G0/G0 APOL1G2/G2 organoids on an isogenic background, performed bulk...
Abstract The renin-angiotensin system (RAS) is essential for normal kidney development. Dysregulation of the RAS during embryogenesis can result in abnormalities. To explore how angiotensin type 1 receptor (AT1R) signaling modulates nephron progenitor (NP) fate specification, we used induced pluripotent stem cell (iPSC) derived human organoids treated with II (Ang II) or AT1R blocker losartan differentiation. Ang promoted NP proliferation and differentiation preferentially towards a podocyte...
It is widely assumed that class I and II Arfs function interchangeably throughout the Golgi complex. However, we report here in vivo, Arf3 displays several unexpected properties. Unlike other Golgi-localized Arfs, associates selectively with membranes of trans-Golgi network (TGN) a manner both temperature-sensitive uniquely dependent on guanine nucleotide exchange factors BIGs family. For example, knockdown redistributed but not Arf1 from membranes. Furthermore, shifting temperature to 20°C,...
COVID-19-associated acute kidney injury (COVID-AKI) is a common complication of SARS-CoV-2 infection in hospitalized patients. The susceptibility human kidneys to direct and modulation the renin-angiotensin II signaling (RAS) pathway by viral remain poorly characterized. Using induced pluripotent stem cell-derived organoids, SARS-CoV-1, SARS-CoV-2, MERS-CoV tropism, defined paired expression host receptor (ACE2, NRP1 or DPP4) protease (TMPRSS2, TMPRSS4, FURIN, CTSB CTSL), was identified...
APOL1 risk variants are associated with increased of kidney disease in patients African ancestry, but not all individuals the high-risk genotype develop disease. As gene expression correlates closely degree cell injury both and animal models, mechanisms regulating may be critical determinants allele penetrance. The messenger RNA includes Alu elements at 3′ untranslated region that can form a double-stranded structure (Alu-dsRNA) susceptible to posttranscriptional adenosine deaminase acting...
Background Mutations in the gene encoding inverted formin-2 (INF2), a member of formin family actin regulatory proteins, are among most common causes autosomal dominant FSGS. INF2 is regulated by interaction between its N-terminal diaphanous inhibitory domain (DID) and C-terminal autoregulatory (DAD). also modulates activity other formins, such as mDIA subfamily, promotes stable microtubule assembly. Why disease-causing mutations restricted to N terminus how they cause human disease has been...
Focal segmental glomerulosclerosis (FSGS) is a histopathologically defined kidney lesion. FSGS can be observed with various underlying causes, including highly penetrant monogenic renal disease. We recently identified pathogenic variants of UMOD, gene encoding the tubular protein uromodulin, in 8 families suspected glomerular disease.To validate we reviewed clinical and pathology reports members to have UMOD. Clinical, laboratory, pathologic data were collected, genetic confirmation for UMOD...
Purpose: Genetic testing results are currently obtained approximately 1 year after referral to a medical genetics team for autosomal dominant polycystic kidney disease (ADPKD). We evaluated mainstream genetic (MGT) pathway whereby the nephrology provided pre-test counseling and selection of patients with suspected ADPKD prior direct patient interaction by geneticist. Sources information: A multidisciplinary nephrologists, counselors, geneticists developed an MGT using current criteria adult...
Absent in melanoma-2 (AIM2) is an inflammasome-forming innate immune sensor for dsDNA but also exhibits inflammasome-independent functions such as restricting cellular proliferation. AIM2 expressed the kidney, its localization and function are not fully characterized. In normal human glomeruli, localized to podocytes. patients with glomerulonephritis, expression increased CD44+-activated parietal epithelial cells within glomerular crescents. To explore effects disease, studies Aim2-/- mice...
This retrospective longitudinal study compared the effectiveness of dexamethasone+lenalidomide (Rd)-based triplet regimens containing proteasome inhibitors (PIs) ixazomib (IRd), carfilzomib (KRd), and bortezomib (VRd) or monoclonal antibodies (MABs) elotuzumab (ERd) daratumumab (DRd) in patients with relapsed/refractory multiple myeloma (RRMM)—including those high cytogenetic risk—primarily treated at community oncology clinics United States. Electronic health records adult RRMM a...