A5010173632- Cell Adhesion Molecules Research
- Renal Diseases and Glomerulopathies
- Glycogen Storage Diseases and Myoclonus
- Platelet Disorders and Treatments
- Metabolism and Genetic Disorders
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Monoclonal and Polyclonal Antibodies Research
- Lysosomal Storage Disorders Research
- Carbohydrate Chemistry and Synthesis
- Vasculitis and related conditions
- Biomedical Research and Pathophysiology
- Diet and metabolism studies
- Renal and related cancers
- Genetics and Neurodevelopmental Disorders
- Blood disorders and treatments
- Autoimmune Bullous Skin Diseases
- Connective tissue disorders research
- Oral and gingival health research
- Genomics and Rare Diseases
- Protease and Inhibitor Mechanisms
- Complement system in diseases
- Neonatal Health and Biochemistry
- Cellular transport and secretion
- Porphyrin Metabolism and Disorders
- Amino Acid Enzymes and Metabolism
Meharry Medical College
2014-2025
Vanderbilt University Medical Center
2002-2016
Vanderbilt University
2003-2013
Hypertension Institute
2013
Matrix Research (United States)
2010-2013
Centro de Investigacion Principe Felipe
2008
Universitat de València
2008
University of Kansas Medical Center
1999-2003
University of Kansas
2000-2001
University of Missouri–Kansas City
1996-1998
MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides distribute kidney inhibit miR-21 function when administered subcutaneously evaluated therapeutic potential these anti-miR-21 chronic disease. In a murine model Alport nephropathy, did not...
In Goodpasture's disease, circulating autoantibodies bind to the noncollagenous-1 (NC1) domain of type IV collagen in glomerular basement membrane (GBM). The specificity and molecular architecture epitopes tissue-bound are unknown. Alport's post-transplantation nephritis, which is mediated by alloantibodies against GBM, occurs after kidney transplantation some patients with syndrome. We compared conformations antibody disease nephritis intention finding clues pathogenesis anti-GBM...
The ultrafiltration function of the glomerular basement membrane (GBM) kidney is impaired in genetic and acquired diseases that affect type IV collagen. GBM composed five (α1 to α5) six chains collagen, organized into an α1·α2(IV) α3·α4·α5(IV) network. In Alport syndrome, mutations any genes encoding α3(IV), α4(IV), α5(IV) cause absence α3·α4·α5 network, which leads progressive renal failure. present study, molecular mechanism underlying network defect was explored by further...
Laminin and type IV collagen composition of the glomerular basement membrane changes during development maturation. Although it is known that both endothelial cells podocytes produce different laminin isoforms at appropriate stages development, cellular origins for heterotrimers appear are unknown. Here, immunoelectron microscopy demonstrated cells, mesangial immature glomeruli synthesize alpha 1 2 alpha1(IV). However, intracellular labeling revealed podocytes, but not or contain 3 4 5(IV)....
Th1 effector CD4+ cells contribute to the pathogenesis of proliferative and crescentic glomerulonephritis, but whether Th17 also is unknown. We compared involvement in a mouse model antigen-specific glomerulonephritis which are only components adaptive immunity that induce injury. planted antigen ovalbumin on glomerular basement membrane Rag1(-/-) mice using an ovalbumin-conjugated non-nephritogenic IgG1 monoclonal antibody against alpha3(IV) collagen. Subsequent injection either Th1- or...
Basement membrane, a specialized ECM that underlies polarized epithelium of eumetazoans, provides signaling cues regulate cell behavior and function in tissue genesis homeostasis. A collagen IV scaffold, major component, is essential for tissues dysfunctional several diseases. Studies bovine Drosophila reveal the scaffold stabilized by sulfilimine chemical bonds (S = N) covalently cross-link methionine hydroxylysine residues at interface adjoining triple helical protomers. Peroxidasin, heme...
The Goodpasture (GP) autoantigen has been identified as the α3(IV) collagen chain, one of six homologous chains designated α1–α6 that comprise type IV (Hudson, B. G., Reeders, S. T., and Tryggvason, K. (1993) J. Biol. Chem. 268, 26033–26036). In this study, chimeric proteins were used to map location major conformational, disulfide bond-dependent GP autoepitope(s) previously localized noncollagenous (NC1) domain chain. Fourteen α1/α3 NC1 chimeras constructed by substituting or more short...
Type IV collagen, the major component of basement membranes (BMs), is a family six homologous chains (α1–α6) that have tissue-specific distribution. The assemble into supramolecular networks differ in chain composition. In this study, novel network was identified and characterized smooth muscle BMs aorta bladder. noncollagenous (NC1) hexamers solubilized by collagenase digestion were fractionated affinity chromatography using monoclonal antibodies against α5 α6 NC1 domains then...
Microscopic polyangiitis is an autoimmune small-vessel vasculitis that often manifests as focal and necrotizing glomerulonephritis renal failure. Antineutrophil cytoplasmic Abs (ANCAs) specific for myeloperoxidase (MPO) play a role in this disease, but the of autoreactive MPO-specific CD4(+) T cells uncertain. By screening overlapping peptides 20 amino acids spanning MPO molecule, we identified immunodominant T-cell epitope (MPO(409-428)). Immunizing C57BL/6 mice with MPO(409-428) induced...
Goodpasture (GP) disease is an autoimmune disorder in which autoantibodies against the α3(IV) chain of type IV collagen bind to glomerular and alveolar basement membranes, causing progressive glomerulonephritis pulmonary hemorrhage. Two major conformational epitope regions have been identified on noncollagenous domain (NC1 domain) as residues 17–31 (E<sub>A</sub>) 127–141 (E<sub>B</sub>) (Netzer, K.-O. <i>et al</i>. (1999)<i>J. Biol. Chem.</i> 274, 11267–11274). To determine whether these...
The middle domain of plasma histidine-proline-rich glycoprotein (HPRG) contains unusual tandem pentapeptide repeats (consensus G(H/P)(H/P)PH) and binds heparin transition metals. Unlike other proteins that interact with via lysine or arginine residues, HPRG relies exclusively on histidine residues for this interaction. To assess the consequences requirement, we have studied interaction between human immobilized glycosaminoglycans (GAGs) using resonant mirror biosensor techniques. binding to...
Membranous nephropathy is an immune kidney disease caused by IgG antibodies that form glomerular subepithelial complexes. Proteinuria mediated complement activation, as a result of podocyte injury C5b-9, but the role specific pathways not known. Autoantibodies mediating primary membranous are predominantly IgG4 subclass, which cannot activate classical pathway. Histologic evidence from biopsies suggests lectin and alternative may be activated in nephropathy, pathogenic relevance these...
The complete primary structure of rabbit plasma histidine−proline-rich glycoprotein (HPRG), also known as histidine-rich glycoprotein, was determined by a combination cDNA and peptide sequencing. Limited proteolysis with plasmin yielded three disulfide-linked fragments that were further purified. Reduction the disulfide bonds dithiothreitol under nondenaturing conditions releases central, domain, which contains 15 tandem repeats pentapeptide [H/P][H/P]PHG. N-terminal fragment (295 amino...
Goodpasture's (GP) disease is caused by autoantibodies that target the alpha3(IV) collagen chain in glomerular basement membrane (GBM). Goodpasture bind two conformational epitopes (E(A) and E(B)) located within non-collagenous (NC1) domain of this chain, which are sequestered NC1 hexamer type IV network containing alpha3(IV), alpha4(IV), alpha5(IV) chains. In study, quaternary organization these chains molecular basis for sequestration were investigated. This was accomplished...
Rapidly progressive glomerulonephritis in Goodpasture disease is mediated by autoantibodies binding to the non-collagenous NC1 domain of alpha3(IV) collagen glomerular basement membrane. epitopes native autoantigen are cryptic (sequestered) within hexamers alpha3alpha4alpha5(IV) network. The biochemical mechanism for crypticity and exposure autoantibody not known. We now report that a feature quaternary structure two distinct subsets hexamers: autoantibody-reactive M-hexamers containing only...
Exogenous soluble human alpha3 noncollagenous (NC1) domain of collagen IV inhibits angiogenesis and tumor growth. These biological functions are attributed to the binding alpha3NC1 integrin alphavbeta3. However, in some cells that express alphavbeta3, does not inhibit proliferation, suggesting alphavbeta3 expression is sufficient mediate anti-tumorigenic activity this domain. Therefore, present study, we searched for novel receptors lacking integrin. In these cells, bound alpha3beta1;...
Mutations in COL4A3/4/5 genes that affect the normal assembly of alpha3/4/5(IV) collagen network glomerular basement membrane (GBM) cause Alport syndrome. Patients progress to renal failure at variable rates are determined by underlying mutation and putative modifier genes. Col4a3(-/-) mice, a model for autosomal recessive syndrome, significantly slower on C57BL/6 than 129X1/Sv background. Reported here is novel strain-specific alternative IV isoform switch associated with differential...
Abstract Germinal matrix is selectively vulnerable to hemorrhage in premature infants, and use of prenatal betamethasone associated with a lower occurrence germinal hemorrhage. Because the major components extracellular cerebral vasculature—laminin, fibronectin, collagen IV, perlecan—provide structural stability blood vessels, we examined whether expression these molecules was decreased affected by betamethasone. In both human fetuses fibronectin significantly than cortical mantle or white...