Imaging proteolytic activity in colon cancer

结肠癌蛋白水解活性成像

• 批准号: 6916429
• 负责人: Khashayarsha Khazaie
• 金额: $ 35.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916429
• 关键词: adenocarcinoma; adenoma; adenomatous polyps; bioimaging /biomedical imaging; cathepsin B; cathepsin D; colon neoplasms; colorectal neoplasms; cysteine endopeptidases; disease /disorder model; endopeptidases; endoscopy; enzyme activity; gastrointestinal epithelium; gastrointestinal imaging /visualization; histology; immunocytochemistry; inflammation; laboratory mouse; metalloendopeptidases; molecular probes; proteolysis

DESCRIPTION (provided by applicant): Colonic adenomas and adenocarcinomas arise as a direct result of stabilization of beta-catenin, often caused by the loss of function of the adenomatous polyposis coli (APC) gene. Indeed, it has been possible to reproduce the full spectrum of aberrant crypt foci, adenoma, carcinoma in mice through spontaneous or conditional mutations of APC, beta-catenin and SMAD4 (a key component of the TGF-beta signaling pathway) genes. Proteolytic enzymes play essential roles in tumor growth, angiogenesis, and invasion and optical in vivo imaging of key enzymes has recently been reported by us (Nature Med 2001; 7, 743-48). Specifically, we have shown that cathepsin B can be used as a highly sensitive imaging marker to detect inflammatory components in dysplastic adenomas (Gastroenterology, 2002; 122, 406- 14). The overall goal of this proposal is to extend our research to systematically explore the role of different cathepsins (D, B, L, K, S) and matrix metalloproteases (2, 7, 8, 9, 13) during colonic tumorigenesis. We hypothesize that some of these probes (e.g. cathepsin B) primarily report inflammation within a lesions, while others (e.g. MMP-7) report on genetically aberrant epithelium. Using mouse models we will screen and catalog lesional protease activities and compare imaging results to accepted gold standards. We subsequently will dissect the cellular components involved in protease production. As proof of principle we will then perform two clinically relevant studies in mouse models a) a screening study involving protease-imaging probes during colonoscopy and b) a study on imaging therapeutic efficacy of non-steroidal anti-inflammatory drugs in polyposis. These preclinical studies will prepare the grounds for near future clinical trials.

描述（由申请人提供）：结肠腺瘤和腺癌是由于β-catenin稳定而产生的，这通常是由于腺瘤性息肉病（APC）基因的功能丧失而引起的。确实，可以通过APC的自发或条件突变，β-catenin和smad4（TGF-beta信号通路的关键成分）基因来重现小鼠异常隐窝灶，腺瘤，小鼠癌。蛋白水解酶在肿瘤生长，血管生成，侵袭和光学在关键酶的体内成像中起着至关重要的作用（Nature Med 2001; 7，743-48）。具体而言，我们已经表明，组织蛋白酶B可以用作高度敏感的成像标记，以检测发育不良腺瘤中的炎症成分（Actroterenterology，2002; 122，406-14）。该提案的总体目标是将我们的研究扩展到系统地探索不同组织蛋白酶（D，B，L，K，S）和基质金属蛋白酶（2、7、8、9、13）的作用。我们假设其中一些探针（例如组织蛋白酶B）主要报告病变内的炎症，而另一些探针（例如MMP-7）报告了遗传异常上皮的报告。使用鼠标模型，我们将筛选和目录病变的蛋白酶活动，并将成像结果与接受的金标准标准进行比较。随后，我们将剖析与蛋白酶产生有关的细胞成分。作为原则的证明，我们将在小鼠模型中进行两项临床相关研究a）筛查研究，涉及结肠镜检查过程中蛋白酶成像探针，b）一项研究在多型息肉病中非甾体类抗炎药的成像治疗功效。这些临床前研究将为不久的将来的临床试验做准备。