Urine Antiproliferative Peptide in Interstitial Cystitis

间质性膀胱炎中的尿液抗增殖肽

• 批准号: 7233286
• 负责人: Susan F. Keay
• 金额: $ 29.56万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7233286
• 关键词: American; Antibodies; Biological; Bladder; Bladder Diseases; Cell Proliferation; Cell membrane; Cells; Chronic; DTR gene; Data; Development; Disease; E-Cadherin; Epidermal Growth Factor; Epithelial; Epithelial Cells; Epithelium; Etiology; Functional disorder; Gene Expression; Glycopeptides; Growth Factor; Growth Inhibitors; Heparin Binding; Heparin Binding Growth Factor; Human; In Vitro; Interstitial Cystitis; JUN gene; Lead; Learning; Life; MAPK8 gene; Malignant Epithelial Cell; Mediating; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Northern Blotting; Pain; Pathogenesis; Patients; Pattern; Peptides; Permeability; Phosphotransferases; Platelet Factor 4; Play; Production; Proteins; Recombinants; Relative (related person); Research Personnel; Role; Sialoglycopeptides; Signal Pathway; Signal Transduction; Structure; Structure-Activity Relationship; Symptoms; Testing; Therapeutic Agents; Tight Junctions; Toxin; Tyrosine; Ulcer; Urine; Ursidae Family; Vertebral column; beta catenin; bladder Carcinoma; claudin 4; design; diphtheria toxin receptor; heparin-binding EGF-like growth factor; in vivo; monolayer; novel; programs; receptor; receptor function; therapy design

DESCRIPTION (provided by applicant): Interstitial cystitis (1C) is a chronic painful bladder disorder with which approximately 1 million Americans are afflicted. The etiology of 1C is unknown, and there is currently no reliably effective treatment. It is therefore important to continue to search for a cause of this debilitating disorder, in order to systematically devise an effective therapy. We have discovered, purified, characterized, and synthesized a toxic glycopeptide (antiproliferative factor, or APF) that appears to be made uniquely by bladder epithelial cells from 1C patients. APF is a small sialoglycopeptide whose peptide backbone bears 100% homology to a segment from the 6th transmembrane portion of Frizzled 8, a receptor that functions in Wnt signalling. APF has been shown to cause specific changes in normal bladder epithelial cells that mimic changes seen in 1C cells in vitro, including profoundly inhibited cell proliferation, specifically altered gene expression, decreased tight junction formation with increased epithelial monolayer permeability, and decreased production of heparin-binding epidermal growth factor-like growth factor (HB-EGF), Because bladder epithelial thinning or ulceration, altered gene expression, leakiness, and decreased urine HB-EGF levels have also been described in 1C patients in vivo, APF may play a direct role in the pathogenesis of 1C. Additional studies on the structure and mechanism of activity for this toxin may therefore be helpful for the development of specific therapies designed to inhibit its activity. Therefore, we propose to learn more about the structure/function relationship of this frizzled-related glycopeptide and the role of specific Wnt signaling pathways in mediating its effects. In addition, we will look for evidence that APF interacts with a specific cell membrane receptor, and determine the relative ability of recombinant human HB-EGF, inactive synthetic APF congeners, and antibodies raised against active synthetic APF congeners to inhibit the effects of APF on bladder epithelial cells. Data from these studies should yield valuable information regarding the structure and mechanism of activity for APF, and may also lead to the identification of potential therapies for this disorder.

描述（由申请人提供）：间质性膀胱炎（1C）是一种慢性疼痛膀胱疾病，大约有100万美国人遭受了困扰。 1C的病因尚不清楚，目前尚无可靠的有效治疗方法。因此，重要的是要继续寻找这种使人衰弱的疾病的原因，以系统地设计有效的疗法。我们已经发现，纯化，表征和合成了有毒糖肽（抗增生因子或APF），这些毒素似乎是由1C患者的膀胱上皮细胞独特地制成的。 APF是一种小的唾液酸糖肽，其肽骨架具有100％同源性，与毛躁8的第6跨膜部分的一部分具有100％同源性，这是一种在Wnt信号传导中起作用的受体。已显示APF在正常膀胱上皮细胞中引起特定变化，表明在1C细胞体外模仿的变化，包括严重抑制的细胞增殖，特异性改变了基因表达，特异性地结构，随着上皮单层的通透性增加，上皮单层的渗透性和增加的产生肝素结构的生长因子（Heparin-Eptermel）生长因子（Hlbland-eperial lib-eper），因为BLADBLADEL或BLADEL-BLADEL-BLADEL或BLADEL-BLADEL-BLADEL或BLADEL-BLADEL-BLADEL eSELEL或BLADEL-BLADEL（因为），因为在1C患者体内，APF的基因表达改变，泄漏和尿液HB-EGF水平的降低也可能在1C的发病机理中发挥直接作用。因此，关于这种毒素活性结构和机制的其他研究可能有助于开发旨在抑制其活性的特定疗法。因此，我们建议更多地了解这种卷曲相关的糖肽的结构/功能关系，以及特定的Wnt信号通路在介导其效果中的作用。此外，我们将寻找证据表明APF与特定的细胞膜受体相互作用，并确定重组人HB-EGF，非活性合成APF同类物以及针对活性合成APF同伴抑制APF对APF对膀胱上皮细胞的影响的相对能力。这些研究的数据应产生有关APF活动的结构和机制的宝贵信息，并且还可能导致鉴定该疾病的潜在疗法。