Urine Antiproliferative Peptide in Interstitial Cystitis

间质性膀胱炎中的尿液抗增殖肽

• 批准号: 7596460
• 负责人: Susan F. Keay
• 金额: $ 28.97万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596460
• 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; effective therapy; 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）是一种慢性疼痛性膀胱疾病，约有100万美国人患有这种疾病。1C的病因不明，目前没有可靠有效的治疗方法。因此，重要的是继续寻找这种使人衰弱的疾病的原因，以便系统地设计有效的治疗方法。我们已经发现，纯化，表征和合成的毒性糖肽（抗增殖因子，或APF），似乎是唯一的膀胱上皮细胞从1C患者。APF是一种小的唾液酸糖肽，其肽骨架与卷曲蛋白8（一种在Wnt信号传导中起作用的受体）的第6个跨膜部分的片段具有100%同源性。已显示APF在正常膀胱上皮细胞中引起特异性变化，其模拟在体外IC细胞中观察到的变化，包括深度抑制细胞增殖、特异性改变基因表达、减少紧密连接形成伴上皮单层通透性增加、以及减少肝素结合表皮生长因子样生长因子（HB-EGF）的产生。在1C患者体内也有基因表达改变、渗漏和尿HB-EGF水平降低的描述，APF可能在1C的发病机制中起直接作用。因此，对这种毒素的结构和活性机制的进一步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糖肽的结构/功能关系以及特定Wnt信号通路在介导其效应中的作用。此外，我们将寻找APF与特定细胞膜受体相互作用的证据，并确定重组人HB-EGF，非活性合成APF同源物和针对活性合成APF同源物的抗体抑制APF对膀胱上皮细胞的影响的相对能力。这些研究的数据应该产生有价值的信息，关于APF的结构和活性机制，也可能导致这种疾病的潜在治疗方法的确定。

项目成果

Quantitative proteomics identifies a beta-catenin network as an element of the signaling response to Frizzled-8 protein-related antiproliferative factor.

定量蛋白质组学将 β-连环蛋白网络确定为对 Frizzled-8 蛋白相关抗增殖因子的信号传导反应的一个要素。

• DOI: 10.1074/mcp.m110.007492
• 发表时间: 2011
• 期刊: Molecular & cellular proteomics : MCP
• 作者: Yang,Wei;Chung,YeunGoo;Kim,Yongsoo;Kim,Taek-Kyun;Keay,SusanK;Zhang,Chen-Ou;Ji,Mihee;Hwang,Daehee;Kim,KwangPyo;Steen,Hanno;Freeman,MichaelR;Kim,Jayoung
• 通讯作者: Kim,Jayoung

Bladder epithelial cells from patients with interstitial cystitis produce an inhibitor of heparin-binding epidermal growth factor-like growth factor production

• DOI: 10.1016/s0022-5347(05)66980-7
• 发表时间: 2000-12-01
• 期刊: JOURNAL OF UROLOGY
• 影响因子: 6.6
• 作者: Keay, S;Kleinberg, M;Warren, JW
• 通讯作者: Warren, JW

A synthetic form of frizzled 8-associated antiproliferative factor enhances p53 stability through USP2a and MDM2.

• DOI: 10.1371/journal.pone.0050392
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kim J;Keay SK;You S;Loda M;Freeman MR
• 通讯作者: Freeman MR

Comparison of APF activity and epithelial growth factor levels in urine from Chinese, African-American, and white American patients with interstitial cystitis.

中国、非裔美国人和美国白人间质性膀胱炎患者尿液中 APF 活性和上皮生长因子水平的比较。

• DOI: 10.1016/s0090-4295(02)02597-9
• 发表时间: 2003
• 期刊: Urology
• 影响因子: 2.1
• 作者: uZhang,Chen-O;Li,Ze-Liang;Shoenfelt,JoannaL;Kong,Chui-Ze;Chai,TobyC;Erickson,DeborahR;Peters,KennethM;Rovner,EricS;Keay,Susan
• 通讯作者: Keay,Susan

Structure-activity relationship studies for the peptide portion of the bladder epithelial cell antiproliferative factor from interstitial cystitis patients.

• DOI: 10.1021/jm8002763
• 发表时间: 2008-10-09
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Kaczmarek P;Keay SK;Tocci GM;Koch KR;Zhang CO;Barchi JJ Jr;Grkovic D;Guo L;Michejda CJ
• 通讯作者: Michejda CJ