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）：该项目是由当前用于评估癌症疗法的体内模型的假设驱动的。这可能成为将新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癌症的新型和类似人类的模型。尽管猪已经在生物医学研究中广泛使用，但迄今为止，尚无报道的癌症转基因猪模型。像人类一样，猪可以生存数十年，并且自发癌的发生率非常低。这与常见的基于啮齿动物的癌症模型相反，该模型仅限于几年，癌症的自发发展很高。我们现在知道，将正常的猪细胞转换为肿瘤细胞需要5-6至6个遗传缺陷。这与人类相同。然而，小鼠细胞可以通过低至两个遗传病变转化为肿瘤细胞。这些简单而深刻的遗传观察表明，猪是人类状况的远远优越的模型系统。我们建议使用最先进的技术来产生转基因猪，这些猪可以同时在乳房中同时失去三个主要肿瘤抑制剂的表达。这些改变将与生长激素受体的上调相结合。这些遗传缺陷通常在乳腺癌，尤其是三重阴性（TN）乳腺癌中发现。 TN乳腺癌是一种特别侵略性且难以治疗乳腺癌的形式，发病率高。我们将在系统中包括一个红色的荧光蛋白，该蛋白将允许对诱导乳腺细胞状态的无创成像进行成像。该项目将涉及实验室的合作，并在人类乳腺癌和实验室的分子和细胞生物学方面具有丰富的经验，以及在转基因猪的生产和饲养世界中的世界知名度。将测试动物，以确定这些病变是否足以促进乳腺癌，以及任何此类癌症是否具有TN乳腺癌的特征。我们还将利用种群测试癌症化学预防剂的有效性，以及猪是否以类似于人类类似的方式对TN乳腺癌的前线治疗做出反应。