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Oncopigs as a better model for human cancer

Oncopigs作为人类癌症的更好模型

基本信息

批准号：
8468132
负责人：
Geoffrey J. Clark
金额：
$ 29.25万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-05 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468132
关键词：
African American Animal Model Animals Arteriosclerosis BRCA1 gene Biological Assay Biological Factors Biological Models Biomedical Research Breast Cancer Model Cells Characteristics Clinical Trials Collaborations Controlled Study Coupled Development Diabetes Mellitus Disease Disease model Effectiveness Epidermal Growth Factor Receptor Failure Family suidae Genetic Growth Hormone Receptor Hand Human Image Laboratories Lesion Life Lipids Lipoproteins Longevity Malignant Neoplasms Metabolism Metastatic malignant neoplasm to brain MicroRNAs Modeling Molecular Molecular and Cellular Biology Monitor Morbidity - disease rate Mus Mutation Neoplasm Metastasis Patients Pharmaceutical Preparations Pilot Projects Population Production Proteins Reporting Rodent Series Staging Study models System Technology Testing Therapeutic Time Tissues Transgenic Organisms Translations Tumor Suppressor Proteins United States Up-Regulation Variant Woman Work arterial lesion base cancer genetics cancer prevention cancer therapy design effective therapy experience expression vector genome sequencing human disease in vivo in vivo Model inhibitor/antagonist interest loss of function malignant breast neoplasm model development mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics predictive modeling public health relevance red fluorescent protein research study success triple-negative invasive breast carcinoma tumor tumorigenesis tumorigenic vector

项目摘要

DESCRIPTION (provided by applicant): This project is driven by the hypothesis that current in vivo models for evaluating cancer therapies are too non-predictive of the human condition for efficient use. This may become a major impediment to the translation of new potential drugs into effective therapies for patients. The project proposes to determine if transgenic pigs may serve as a novel and more human-like model for cancer. Although pigs have been used extensively in biomedical research, to date, there is no reported transgenic swine model for cancer. Like humans, pigs can live for decades and have a very low rate of spontaneous cancer. This is in contrast to common rodent-based cancer models, where life span is limited to a few years and the spontaneous development of cancer is quite high. We now know that 5-6 to six genetic defects are required to convert a normal pig cell into a tumor cell. This is the same as in humans. However, mouse cells can be transformed into tumor cells by as little as two genetic lesions. These simple yet profound genetic observations point to pigs as a far superior model system for the human condition. We propose to use state of the art technology to generate transgenic pigs that can be induced to lose the expression of three major tumor suppressors simultaneously in the breast. These alterations will be coupled with an up-regulation of a growth hormone receptor. These genetic defects are often found in breast cancer and particularly in Triple Negative (TN) breast cancer. TN breast cancer is an especially aggressive and difficult to treat form of breast cancer with a high morbidity rate. We will include a far red fluorescent protein in the system which will allow non-invasive imaging of the status of the induced breast cells. The project will involve the collaboration of laboratories with extensive experience in the molecular and cellular biology of human breast cancer and laboratories with world renown in the production and husbandry of transgenic pigs. Animals will be tested to determine if these lesions are sufficient to provoke breast cancer and whether any such cancers have the characteristics of TN breast cancer. We will also use the population to test the effectiveness of cancer chemopreventative agents, and whether the pigs respond to front line therapy for TN breast cancer in a similar manner to humans.

描述（由申请人提供）：该项目的假设是，当前用于评估癌症治疗的体内模型对于人类状况的预测性太差，无法有效使用。这可能成为将新的潜在药物转化为患者有效疗法的主要障碍。该项目提议确定转基因猪是否可以作为一种新颖的、更类似于人类的癌症模型。尽管猪已广泛用于生物医学研究，但迄今为止，还没有关于癌症的转基因猪模型的报道。与人类一样，猪可以存活数十年，并且自发性癌症的发生率非常低。这与常见的基于啮齿动物的癌症模型形成鲜明对比，后者的寿命仅限于几年，并且癌症的自发发展相当高。我们现在知道，将正常猪细胞转化为肿瘤细胞需要 5-6 到 6 个遗传缺陷。这与人类相同。然而，小鼠细胞只要经过两次基因损伤就可以转化为肿瘤细胞。这些简单而深刻的遗传观察表明，猪是人类状况的一个更优越的模型系统。我们建议使用最先进的技术来产生转基因猪，这些猪可以被诱导在乳房中同时失去三种主要肿瘤抑制因子的表达。这些改变将与生长激素受体的上调相结合。这些遗传缺陷经常出现在乳腺癌中，尤其是三阴性 (TN) 乳腺癌中。 TN 乳腺癌是一种特别具有侵袭性且难以治疗的乳腺癌，发病率很高。我们将在系统中加入远红荧光蛋白，这将允许对诱导乳腺细胞的状态进行非侵入性成像。该项目将涉及在人类乳腺癌分子和细胞生物学方面拥有丰富经验的实验室以及在转基因猪生产和饲养方面世界知名的实验室的合作。将对动物进行测试，以确定这些病变是否足以引发乳腺癌，以及此类癌症是否具有 TN 乳腺癌的特征。我们还将利用该群体来测试癌症化学预防剂的有效性，以及猪是否以与人类类似的方式对 TN 乳腺癌一线治疗产生反应。