INNOVATIVE INTRAVESICAL TREATMENT APPROACH FOR IC

IC 的创新膀胱内治疗方法

• 批准号: 6178242
• 负责人: VEER P. BHAVANANDAN
• 金额: $ 11.75万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178242
• 关键词: N acetylglucosamine; binding sites; chemotherapy; galactose; human tissue; interstitial cystitis; laboratory rabbit; lectin; ligands; nonhuman therapy evaluation; northern blottings; polysaccharides; protein localization; protein structure function; urinary bladder; urinary bladder epithelium

Interstitial cystitis is poorly understood, and the causes and pathophysiology for IC are still unknown. Many theories have been proposed about the etiology of IC, but none has been definitively proven. There are no cures for IC and clinicians use a variety of empiric treatments, based on the proposed causes for IC. However, none of these treatments are consistently effective, and some patients remain unable to find any relief. One popular theory about IC is that the glycocalyx of the bladder epithelium is deficient. Accordingly, some of the current treatments are aimed at replacing the missing glycoconjugates by intravesical or oral administration of sulfated polysaccharides, such as heparin and pentosan polysulfate (Elmiron). It is unknown why these treatments show improvement of symptoms in only some IC patients, and why the response is usually slow. One possible reason is that the highly anionic and readily water-soluble sulfated polysaccharides do not adhere to the bladder well enough to exert their beneficial effect. An exploratory study is proposed for the development of an innovative approach that should not only increase the efficiency of sulfated polysaccharides for patients who respond, but may also benefit some patients who do not currently respond. The plan is to improve the binding and thereby strengthen and prolong the adherence of intravesically administered drugs to the bladder. The experimental strategy is to modify the sulfated polysaccharides with specific saccharide ligands, so that they will bind to endogenous lectins in the bladder. In order to choose the saccharide structures for this purpose it is first necessary to identify the lectins present in the bladder epithelium of rabbit (an animal model for initial binding studies) and human. Preliminary studies have demonstrated the presence of galactose- and N-acetylglucosamine-binding lectins in both rabbit and human bladders. Further detailed investigations are needed to complete the biochemical characterization of the major bladder lectins and specifically, elucidate their saccharide specificities. Once identified, the saccharide ligands will be conjugated to sulfated polysaccharides and the binding of the conjugates to bladder will be evaluated. Although the initial studies will be on sulfated polysaccharide treatments of IC, the same strategy could also be applied to improve treatment of various other bladder diseases. For example, prolonged binding of antibiotics to the urothelium may help to treat or prevent urinary tract infections.

间质性膀胱炎的理解很少，IC的原因和病理生理学仍然尚不清楚。 已经提出了许多关于IC病因的理论，但没有一个被确定的证明。 IC没有治疗方法，临床医生根据提议的IC原因使用各种经验治疗。 但是，这些治疗方法均未始终有效，有些患者仍无法找到任何缓解。关于IC的一种流行理论是，膀胱上皮的糖蛋白是不足的。 因此，某些当前治疗方法旨在通过静脉内或口服硫酸化多糖（例如肝素和五角星多硫酸盐（Elmiron））代替缺失的糖缀合物。 尚不清楚这些治疗方法仅在某些IC患者中显示出症状的改善，以及为什么反应通常很慢。 一个可能的原因是，高度阴离子和易于水溶性的硫化多糖不能很好地粘附在膀胱上，无法发挥其有益作用。 提出了一项探索性研究，以开发一种创新方法，该方法不仅应提高反应式患者硫酸多糖的效率，而且还可能使某些目前没有反应的患者受益。 该计划是改善结合，从而增强和延长插入性药物对膀胱的遵守。 实验策略是用特异性的糖配体修饰硫酸化的多糖，以便它们与膀胱中的内源性凝集素结合。 为了为此目的选择糖结构，首先有必要识别兔上皮中存在的凝集素（用于初始结合研究的动物模型）和人类。初步研究表明，兔和人膀胱中都存在半乳糖和N-乙酰葡萄糖结合凝集素。 需要进一步的详细研究来完成主要膀胱凝集素的生化表征，具体来说，阐明了它们的糖特异性。 一旦确定，糖配体将与硫酸化的多糖结合，并评估结合物与膀胱的结合。 尽管最初的研究将是关于IC的硫酸多糖治疗方法，但也可以采用相同的策略来改善对其他各种膀胱疾病的治疗。例如，抗生素长期结合与尿路上皮可能有助于治疗或预防尿路感染。