Optical Imaging of Ovarian Carcinogenesis in a Rat Menopause Model

描述（由申请人提供）：卵巢癌在所有妇科癌症中死亡率最高，70%的卵巢癌患者在5年内死于该病。早期疾病的生存率很高，但卵巢癌通常不会在III期或IV期之前被发现，因为它的表现是模糊的，卵巢难以进入，并且对浸润前病变知之甚少。由于缺乏适当的和良好表征的动物模型，对卵巢癌病因学的理解以及对这种疾病的有效检测和治疗的努力受到阻碍。最近，有报道称，将啮齿动物卵巢直接暴露于低剂量致癌物7，12-二甲基苯并[a]蒽（DMBA）的模型会出现类似人类的（前）肿瘤病变。我们正在通过将其与卵泡耗竭、卵巢完整的绝经大鼠模型相结合来改进这种致癌物模型。这一改进的模型将有助于确定绝经后妇女对卵巢癌的不同易感性。这项研究的总体目标是开发对抗卵巢癌所急需的两种能力：1）与人类疾病非常相似的卵巢癌大鼠模型，2）对早期肿瘤变化敏感的微创成像方式。我们希望我们的研究有助于识别预测癌症的早期肿瘤变化。该提案有四个具体目标：1。建立围绝经期和绝经后大鼠卵巢癌模型。将确定使用4-乙烯基环己烯二环氧化物（VCD）和DMBA建立新型卵巢完整大鼠绝经模型的最佳剂量、给药和时间。将评价解剖学和生化变化。2.开发光学成像技术，以实现高分辨率的体外和体内时间序列 大鼠卵巢成像。微型光学相干断层扫描（OCT），激光诱导荧光（LIF）和高分辨率光学相干显微镜（OCM）将被开发，使我们的改进的动物模型微创成像。3.确定造影剂在正常卵巢组织、卵泡缺失卵巢组织和癌性卵巢组织中的作用机制。我们将进行一项全面的离体研究，以阐明3种成像方式中的对比机制。developed.in 4.进行卵巢癌发生的体内连续成像研究。我们将进行微创，时间序列成像，以跟踪我们的大鼠模型的致癌作用。本研究的目的是确定OCT、OCM或LIF上可见的早期解剖学或生化变化，以预测肿瘤的未来发展，并确定循环和卵泡耗竭动物的病变时间顺序是否不同。

DESCRIPTION (provided by applicant): Ovarian cancer has the highest mortality of all gynecologic cancers, and 70% of women with ovarian cancer die of their disease within 5 years. Survival is high with early stage disease, yet ovarian cancer is not usually detected earlier than Stage III or IV because its presentation is vague, the ovary is difficult to access, and little is known about preinvasive lesions. Efforts to understand ovarian cancer etiology and to develop effective detection and treatments for this disease have been hampered by lack of appropriate and wellcharacterized animal models. Recently, models that directly expose the rodent ovary to low doses of the carcinogen 7,12--Dimethylbenz[a]anthracene (DMBA) have been reported to develop human-like (pre)neoplastic lesions. We are improving upon this carcinogen model by combining it with a follicle-deplete, ovary-intact rat model of menopause. This improved model will be useful for determining the differential susceptibility of post-menopausal women to ovarian cancer. The overall goal of this research is to develop 2 capabilities critically needed in the fight against ovarian cancer: 1) a rat model of ovarian cancer that closely resembles the human disease, and 2) minimally-invasive imaging modalities sensitive to early neoplastic changes. We expect our research aid in identification of early neoplastic changes that predict cancer. This proposal has 4 specific aims: 1. Develop a peri-and post-menopausal rat ovarian cancer model. Optimum dosing, administration and timing will be determined for the creation of a novel ovary-intact rat model of menopause using 4-Vinylcyclohexene Diepoxide (VCD) and DMBA. Anatomical and biochemical changes will be evaluated. 2. Develop optical imaging technologies to permit high resolution ex vivo and time-serial in vivo imaging of rat ovary. Miniaturized optical coherence tomography (OCT), laser induced fluorescence (LIF), and high resolution optical coherence microscopy (OCM) will be developed to enable minimally invasive imaging in our improved animal model. 3. Determine mechanisms of contrast in normal, follicle deplete, and cancerous ovarian tissues. We will undertake a comprehensive ex vivo study to elucidate mechanisms of contrast in the 3 imaging modalities developed.in specific aim 2. 4. Perform in vivo, serial imaging studies of ovarian carcinogenesis. We will perform minimallyinvasive, time-serial imaging order to follow carcinogenesis in our rat models. The goal of this study is to determine early anatomical or biochemical changes visible on OCT, OCM, or LIF that predict future development of neoplasms, and to determine if the time sequence of lesions is different for cycling and follicle-deplete animals.