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Studies on the Structure of Basement Membranes

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

KETCHUM, CHRISTIAN J.

项目受资助机构

VANDERBILT UNIVERSITY MEDICAL CENTER

项目编号

3R01DK018381-48S1

立项年度

2019

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

46847.00美元

学科

Biotechnology;Kidney Disease

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

HUDSON, BILLY GERALD

参与机构

NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

项目标书摘要：?DESCRIPTION (provided by applicant): Diseases of the glomerulus, the filtering unit of the kidney, account for over 60% of all cases of end-stage renal disease, which represents a major health problem worldwide. Among them are Goodpasture's (GP) disease, Alport syndrome and diabetic nephropathy that damage the glomerular basement membrane (GBM) through pathogenic mechanisms involving collagen IV scaffolds. This proposal focuses on the collagen IV scaffolds with the overall goal to gain a deeper insight into fundamental mechanisms of molecular recognition, at the atomic level, that underlie normal assembly, function and dysfunction of the scaffolds. Our recent discoveries reveal a GP autoantigen complex that plays a central role in GBM function and in the pathogenesis in GP and Alport diseases. This complex now serves as the cornerstone for four Specific Aims that target an understanding of the chemistry and pathology of each component. The knowledge gained will provide a framework for development of new forms of therapy. Aim 1: To determine the molecular structure of GP epitopes of ?345 collagen IV network and role of GP antibody in pathogenesis. We identified four homologous hotspot regions within ?3NC1 and ?5NC1 monomers that are key for GP antibody binding and have cloned first human GP monoclonal antibody. We hypothesize that the full epitopes are formed upon the change in antigen conformation and that epitope-specific GP mAbs will induce renal failure. Aim 2: To determine the impact of PXDN dysregulation on ?345 collagen IV networks. We discovered that PXDN catalyzes ?121 sulfilimine crosslinks, requires Br, makes HOBr, and anti-PXDN antibodies occur in GP sera. We hypothesize that PXDN crosslinks ?345 collagen IV through an enzyme-substrate complex, and that perturbation of this complex creates oxidative protein modifications on collagen IV. Aim 3: To determine whether GP epitope formation requires phosphorylation by GPBP. GPBP has emerged as a nonconventional kinase that binds and phosphorylates the GP autoantigen and influences the assembly of collagen IV networks. We hypothesize that GPBP phosphorylation alters the presentation of Ea and Eb epitopes and promotes autoantibody binding to ?3NC1. Aim 4: To determine the NC1-mediated mechanism for assembly of the collagen IV ?345 network. We discovered that NC1 domains of collagen IV function as assembly recognition modules. We hypothesize that NC1 domains mediate the assembly of protomers and networks by distinct mechanisms, which are disrupted in disease.

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  • 1.Halogens are key cofactors in building of collagen IV scaffolds outside the cell

    • 关键词：
    • bromine; chlorine; collagen IV scaffold; glomerular basement membrane;halogenation; halogens;GLOMERULAR-BASEMENT-MEMBRANE; EXTRACELLULAR-MATRIX; HYPOHALOUS ACIDS;MYELOPEROXIDASE; PEROXIDASIN; PROTEINS; CHLORIDE; NETWORK; KIDNEY;DAMAGE

    Purpose of reviewThe purpose of this review is to highlight recent advances in understanding the molecular assembly of basement membranes, as exemplified by the glomerular basement membrane (GBM) of the kidney filtration apparatus. In particular, an essential role of halogens in the basement membrane formation has been discovered.Recent findingsExtracellular chloride triggers a molecular switch within non collagenous domains of collagen IV that induces protomer oligomerization and scaffold assembly outside the cell. Moreover, bromide is an essential cofactor in enzymatic cross-linking that reinforces the stability of scaffolds. Halogenation and halogen-induced oxidation of the collagen IV scaffold in disease states damage scaffold function.SummaryHalogens play an essential role in the formation of collagen IV scaffolds of basement membranes. Pathogenic damage of these scaffolds by halogenation and halogen-induced oxidation is a potential target for therapeutic interventions.

    ...

  • 2.Halogens are key cofactors in building of collagen IV scaffolds outside the cell

    • 关键词：
    • bromine; chlorine; collagen IV scaffold; glomerular basement membrane;halogenation; halogens;GLOMERULAR-BASEMENT-MEMBRANE; EXTRACELLULAR-MATRIX; HYPOHALOUS ACIDS;MYELOPEROXIDASE; PEROXIDASIN; PROTEINS; CHLORIDE; NETWORK; KIDNEY;DAMAGE

    Purpose of reviewThe purpose of this review is to highlight recent advances in understanding the molecular assembly of basement membranes, as exemplified by the glomerular basement membrane (GBM) of the kidney filtration apparatus. In particular, an essential role of halogens in the basement membrane formation has been discovered.Recent findingsExtracellular chloride triggers a molecular switch within non collagenous domains of collagen IV that induces protomer oligomerization and scaffold assembly outside the cell. Moreover, bromide is an essential cofactor in enzymatic cross-linking that reinforces the stability of scaffolds. Halogenation and halogen-induced oxidation of the collagen IV scaffold in disease states damage scaffold function.SummaryHalogens play an essential role in the formation of collagen IV scaffolds of basement membranes. Pathogenic damage of these scaffolds by halogenation and halogen-induced oxidation is a potential target for therapeutic interventions.

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