Novel peptide-based strategy to inhibit deleterious TNF signaling in nephrotoxic nephritis

基于肽的新型策略抑制肾毒性肾炎中有害的 TNF 信号传导

• 批准号: 9296123
• 负责人: Rudolf Lucas
• 金额: $ 22.8万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296123
• 关键词: Acute Glomerulonephritis; Adverse effects; Affect; Albuminuria; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Bacterial Infections; Binding; Biological Preservation; CCL2 gene; Cells; Collagen; Complex; Conduct Clinical Trials; Coupled; Coupling; Development; Dinoprostone; Disease; Disease Progression; Edema; Endothelial Cells; Epithelial; Epitopes; Etiology; Functional disorder; Generations; Glomerular Filtration Rate; Glomerulonephritis; Goals; Human; Immune; Immune Complex Glomerulonephritis; Immunosuppressive Agents; Impairment; In Vitro; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-6; Kidney; Kidney Diseases; Kidney Failure; Knock-in; Knock-in Mouse; Knowledge; Lead; Lectin; Leukocytes; Ligand Binding; Link; MAPK14 gene; Mediating; Mediator of activation protein; Methods; Modeling; Mus; Nephritis; Nephrotoxic; Onset of illness; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Physiological; Play; Predisposition; Property; Proteinuria; Reagent; Recruitment Activity; Renal function; Renal glomerular disease; Risk; Role; Serum; Signal Transduction; Steroids; Stress; TNF gene; TNFRSF1A gene; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Tumor Necrosis Factor Receptor; Western Blotting; Wild Type Mouse; base; caveolin 1; chemokine; comparative efficacy; conventional therapy; cytokine; experimental study; improved; in vivo; macrophage; mimetics; mitogen-activated protein kinase p38; mutant; nephrotoxicity; novel; novel therapeutic intervention; novel therapeutics; overexpression; peptide drug; podocyte; prevent; promoter; protective effect; protective efficacy; public health relevance; receptor; repaired; synaptopodin; targeted treatment; therapeutic target

 DESCRIPTION (provided by applicant): The early stage of nephrotoxic serum (NTS)-induced nephritis (NTN) in mice is characterized by excessive inflammation and glomerular barrier dysfunction and represents a good model for human acute glomerulonephritis (GN). Glomerular endothelial and epithelial compartments represent attractive targets for early therapeutic intervention, due to their crucial roles in the recruitment of leukocytes, proteinuria and progressive renal failure. Current therapies aiming to treat or prevent progression of the disease are insufficient and limited, stressing the need for novel therapeutic approaches that control inflammation associated with GN. In this context, the cytokine TNF is an ideal target, since it is critically involved in both human GN and in murine NTN. Unfortunately, attempts to blunt TNF binding to its receptors for the treatment of GN were met with unexpected side effects, including increased risk for bacterial infection. Therefore, therapies that specifically target the deleterios effects of TNF, but leave its beneficial effects intact are desirable. Our preliminary studies indicate that the TIP peptide, which mimics TNF's lectin-like domain and which does not interfere with the ligand's binding to its receptors, interferes with at least two pathways importat in podocyte and glomerular endothelial cells (GEC) demise in NTN. On the one hand, the peptide blunts the p38 pro-inflammatory pathway in GEC, important for the generation of pro-inflammatory mediators, for the induction of eNOS dysfunction and for leukocyte infiltration. On the other hand, TIP peptide protects podocyte barrier function, possibly means by inducing PGE2 generation in podocytes, shown to be protective in NTN. In the early phase of NTN, the peptide blunts systemic generation of TNF, IL-6 and MCP-1, reduces macrophage infiltration, edema formation, restores glomerular filtration rate and synaptopodin expression and abrogates albuminuria. Our central hypothesis is that the TIP peptide protects the kidney against NTN by suppressing TNF-induced activation of pro-inflammatory and barrier-disruptive pathways in GEC and podocytes, respectively, as such blunting leukocyte infiltration and glomerular injury, without interfering with the anti-bacterial actions of the cytokine. In our three specific aims, we will combine in vivo proof-of-concept NTN mouse studies (aims 1 and 2) podocyte- and GEC-based with mechanistic in vitro cell studies (aim 3). We will use unique models and reagents, such as knock-in mice expressing a TNF mutant without functional lectin-like domain (aim 2). Moreover, we will assess local vs. systemic effects of the peptide upon comparing the efficacy of anti-3(IV) antibody-coupled vs. naked TIP peptide (aim 1A) and testing the peptide in a renal local inflammation model, initiated by endothelial overexpression of transmembrane TNF (aim 1B). Understanding the mechanism of TIP peptide- mediated protective effects against auto-immune GN will advance our knowledge on the inflammatory and anti- inflammatory pathways relevant for nephropathy and will help to conduct clinical trials to determine the efficacy of novel therapeutic peptides against other immune, inflammatory diseases.



项目成果

Cytokine-Ion Channel Interactions in Pulmonary Inflammation.

• DOI: 10.3389/fimmu.2017.01644
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Hamacher J;Hadizamani Y;Borgmann M;Mohaupt M;Männel DN;Moehrlen U;Lucas R;Stammberger U
• 通讯作者: Stammberger U

Restoration of Epithelial Sodium Channel Function by Synthetic Peptides in Pseudohypoaldosteronism Type 1B Mutants.

• DOI: 10.3389/fphar.2017.00085
• 发表时间: 2017
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Willam A;Aufy M;Tzotzos S;Evanzin H;Chytracek S;Geppert S;Fischer B;Fischer H;Pietschmann H;Czikora I;Lucas R;Lemmens-Gruber R;Shabbir W
• 通讯作者: Shabbir W