Mechanisms of Early Stage Mammary Tumorigenesis

早期乳腺肿瘤发生机制

基本信息

  • 批准号:
    8349440
  • 负责人:
  • 金额:
    $ 59.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

There are several components to this project. Development of new imaging techniques for detection and characterization of preinvasive and early invasive mammary cancers in mice: We are developing magnetic resonance (MR) imaging, ultrasound (US) imaging, and intravital microscopy (IVM) techniques for the detection of early stage mammary cancers in mice. The purpose of developing these new imaging techniques is two-fold: (i) to perform in vivo characterization of early mammary tumorigenesis in mouse models of breast cancer (see next project below) for which imaging techniques are necessary since early stage cancers are too small to be visible by eye or palpated, and (ii) to use mouse models as a test-bed for developing new imaging strategies that can be applied in women. In addition to developing new imaging acquisition techniques, we are also developing a Mulitmodality Mouse Imaging Workstation to improve image analysis and data storage. We are currently performing a study evaluating noncontrast MR and US imaging in wild-type mice, xenograft models and transgenic models; in doing so, we have successfully developed a new strategy for performing MR/US/histology correlations using an agar grid. Upon successful completion of this pilot study, we will begin to develop US contrast-enhanced techniques for quantifying lesion vasculature in a collaboration with Paul Dayton. We have also established a collaboration with Roberto Weigert to begin IVM of the mouse mamamry glands. Investigate cell-type susceptibility in new mouse models of breast cancer: The normal human breast can be broadly characterized as being comprised of epithelial cells that express cytokeratins K18/K8 (luminal cells) and K5/K14 (basal and some epithelial cells). Some intermediate epithelial cells are known to co-express K5/K18 as well as other keratins such as K19. To determine the role of cell-type susceptibility in mammary tumorigenesis, we have developed mouse models which drive expression of a conditional T121 allele thus functionally inactivating the pRb pathway, known to be frequently altered in human breast cancer--to specific cell types under control of K18, K19 and K5 regulation (please see Project 1 for a description of these models, and crosses with prostate-specific Cre lines to drive prostate tumorigenesis). We are currently breeding these mice to mammary specific Cre lines to drive cell-type-specific, mammary-specific tumorigenesis, and have also crossed the mice to p53 conditional knockout mice to determine if the tumor phenotype can be accelerated with p53 loss. Mice with tumors will be dissected and tissues processed for pathologic and molecular analysis. We will also be applying the imaging techniques developed above to characterize the timescales of early stage tumorigenesis and progression in these different mouse models. While waiting for these mice to develop, we are performing a study of the distribution of K5, K18 and K19 cells in the normal mouse mammary gland. Quantify lesion physical properties and assess role in progression: In addition to studying the molecular and genetic characteristics of early stage tumors, we are also interested in determining the role of lesion physical properties during progression of preinvasive lesions. In general, most imaging techniques provide a direct reflection of the physcial properites of tissues: for MRI, the tissue magnetic relaxation parameters T1, T2 or proton density p; for US, their acoustic properties. Thus, the noncontrast MR and US imaging we are currently developing already provide a physical characterization. We are also interested in developing advanced techniques to quantify physical lesion properties--such as stiffness (from US elastography) and basement membrane permeability (from IVM). Such physical characteristics of lesions can be noninvasively assessed with in vivo imaging, and thus changes in these properties can be assessed over time to determine if any are predictive of progression. We will commence this project upon successful completion of the MR/US pilot study outlined above.
这个项目有几个组成部分。开发新的成像技术用于检测和表征小鼠早期浸润性乳腺癌:我们正在开发磁共振(MR)成像、超声(US)成像和活体显微镜(IVM)技术,用于检测小鼠早期乳腺癌。开发这些新的成像技术的目的有两个:(I)在小鼠乳腺癌模型(见下文)中对早期乳腺癌的发生进行体内表征,由于早期乳腺癌太小,肉眼无法看到或无法触摸到,因此成像技术是必要的;(Ii)将小鼠模型用作试验床,以开发可应用于女性的新成像策略。除了开发新的成像采集技术外,我们还在开发多通道鼠标成像工作站,以改进图像分析和数据存储。我们目前正在进行一项研究,评估野生型小鼠、异种移植模型和转基因模型的非对比MR和US成像;通过这样做,我们成功地开发了一种使用琼脂网格进行MR/US/组织学关联的新策略。在这项初步研究成功完成后,我们将与Paul Dayton合作,开始开发美国对比剂增强技术来量化病变血管。我们还与Roberto Weigert建立了合作关系,开始小鼠乳房腺的IVM。在新的乳腺癌小鼠模型中研究细胞类型的敏感性:正常的人类乳房可以广泛地描述为由表达细胞角蛋白K18/K8(腔细胞)和K5/K14(基底细胞和一些上皮细胞)的上皮细胞组成。已知一些中间上皮细胞共表达K5/K18以及其他角蛋白,如K19。为了确定细胞类型的易感性在乳腺肿瘤发生中的作用,我们开发了一些小鼠模型,它能够驱动条件T121等位基因的表达,从而在功能上灭活已知在人类乳腺癌中经常改变的pRB通路--在K18、K19和K5调控下的特定细胞类型(请参阅项目1了解这些模型的描述,并与前列腺特异的Cre系杂交以驱动前列腺癌的形成)。我们目前正在将这些小鼠培育到乳腺特异的Cre系,以驱动特定细胞类型的、乳腺特异的肿瘤发生,并将这些小鼠与P53条件基因敲除小鼠杂交,以确定是否可以在P53丢失的情况下加速肿瘤表型。携带肿瘤的小鼠将被解剖,并对组织进行病理和分子分析。我们还将应用上面开发的成像技术来表征这些不同小鼠模型的早期肿瘤发生和进展的时间尺度。在等待这些小鼠发育的同时,我们正在对K5、K18和K19细胞在正常小鼠乳腺中的分布进行研究。量化病变物理特性并评估进展中的作用:除了研究早期肿瘤的分子和遗传特征外,我们还对确定病变物理特性在侵袭前病变进展中的作用感兴趣。一般来说,大多数成像技术提供了对组织物理特性的直接反映:对于MRI,组织磁弛豫参数t1、t2或质子密度p;对于US,它们的声学特性。因此,我们目前正在开发的非对比MR和US成像已经提供了物理特征。我们还对开发先进的技术来量化物理损伤属性感兴趣--例如硬度(来自US弹性成像)和基底膜通透性(来自IVM)。这种损伤的物理特征可以用活体成像进行非侵入性的评估,因此可以随着时间的推移评估这些属性的变化,以确定是否有预测进展的因素。我们会在上述MR/US试验研究成功完成后,展开这项计划。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Terry van Dyke其他文献

Terry van Dyke的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Terry van Dyke', 18)}}的其他基金

Rb TS inhibition dedifferentiates astrocytes leading to Astrocytoma initiation
Rb TS 抑制使星形胶质细胞去分化,导致星形细胞瘤发生
  • 批准号:
    8763536
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
Mechanisms of Prostate Tumorigenesis Using Genetically Engineered Mouse Models
使用基因工程小鼠模型研究前列腺肿瘤发生机制
  • 批准号:
    8552875
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
The study of underlying mechanism of EGFR-Ras signaling in glioblastoma
胶质母细胞瘤中EGFR-Ras信号传导机制的研究
  • 批准号:
    8552936
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
Pathway Analysis in Mouse Model for Astrocytoma via Systems Biology Approach
通过系统生物学方法对星形细胞瘤小鼠模型进行通路分析
  • 批准号:
    8938029
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
Development of ESiPSC approach for non-germline GEM modeling
开发用于非种系 GEM 建模的 ESiPSC 方法
  • 批准号:
    8938101
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
Pathway Analysis in Mouse Model for Astrocytoma via Systems Biology Approach
通过系统生物学方法对星形细胞瘤小鼠模型进行通路分析
  • 批准号:
    8349422
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
Development of ESiPSC approach for non-germline GEM modelling
开发用于非种系 GEM 建模的 ESiPSC 方法
  • 批准号:
    8349534
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
Development and validation of preclinical mouse model for serous ovarian cancer
浆液性卵巢癌临床前小鼠模型的开发和验证
  • 批准号:
    8349495
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
The Mechanism of Thymic Lymphomagenesis in Genetically Engineered Mouse Model
基因工程小鼠模型胸腺淋巴瘤发生机制
  • 批准号:
    8349382
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:
Establishing the Preclinical Model for Metastatic Melanoma
建立转移性黑色素瘤的临床前模型
  • 批准号:
    8553206
  • 财政年份:
  • 资助金额:
    $ 59.63万
  • 项目类别:

相似国自然基金

Cd(II)在NH2-Agar/PSS双网络水凝胶上的吸附行为及资源化工艺研究
  • 批准号:
    51708204
  • 批准年份:
    2017
  • 资助金额:
    25.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

An ethnographic study on the utilization and allocation of sea resources among agar divers in Japan, Taiwan and Korea
日本、台湾、韩国琼脂潜水者海洋资源利用与配置的人种学研究
  • 批准号:
    19K13467
  • 财政年份:
    2019
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Edible optical systems made of agar
由琼脂制成的可食用光学系统
  • 批准号:
    18K19799
  • 财政年份:
    2018
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
Agar-based gel-electrolytes for corrosion diagnostic
用于腐蚀诊断的琼脂基凝胶电解质
  • 批准号:
    330472124
  • 财政年份:
    2017
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Research Grants
Micro-Patterning of Agar Surface for Cultivation Control of Microbes
用于微生物培养控制的琼脂表面微图案化
  • 批准号:
    15K14703
  • 财政年份:
    2015
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Elucidation of the mechanism that heterotrophic bacteria induce the growth of the cyanobacterial strain on agar media
阐明异养细菌诱导蓝藻菌株在琼脂培养基上生长的机制
  • 批准号:
    26650166
  • 财政年份:
    2014
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
The Production of Japanese Agar and Gelatin in Edo Period
江户时代日本琼脂和明胶的生产
  • 批准号:
    21520663
  • 财政年份:
    2009
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Organization of Novel Marine Bacterial Structures Involved in the Degradation of Agar
参与琼脂降解的新型海洋细菌结构的组织
  • 批准号:
    0109869
  • 财政年份:
    2001
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Continuing Grant
Swallowing Characteristics of Bolus of Agar Gels on the Swallowing Process
琼脂凝胶丸剂对吞咽过程的吞咽特性
  • 批准号:
    09680040
  • 财政年份:
    1997
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
HIGH FREQUENCY FLUX CONTROL OF MAGNETIC AGAR USING PLANT MAGNETIC MATERIAL AND ITS APPLICATIONS
植物磁性材料对磁性琼脂的高频通量控制及其应用
  • 批准号:
    08555095
  • 财政年份:
    1996
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Raum-Zeit-Strukturen von Ca2+-Signalen in einem SR-Vesikel-Agar-System; Experimente und Modellierung
SR囊泡琼脂系统中Ca2信号的时空结构;
  • 批准号:
    5194244
  • 财政年份:
    1995
  • 资助金额:
    $ 59.63万
  • 项目类别:
    Research Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了