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Transcription Factor Reporter Technology

转录因子报告技术

基本信息

批准号：
7849683
负责人：
Alexei A Bogdanov
金额：
$ 27.61万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849683
关键词：
Animals Binding Binding Sites Biocompatible Biodistribution Boxing Cell Adhesion Cell Line Cells Chemistry DNA Binding Development Dissection Enzymes Family Fluorescence Fluorescence Polarization Fluorescence Resonance Energy Transfer Fluorescent Probes Fluorochrome Gene Expression Genes Genetic Transcription Human Image Imaging technology In Vitro Lead Life Malignant Neoplasms Measurement Measures Methods Modeling Molecular Molecular Genetics NF-kappa B Nuclear Oligonucleotide Probes Oligonucleotides Pathway interactions Pharmaceutical Chemistry Phenotype Play Property Protein Binding Proteins Radioisotopes Recombinants Regulation Reporter Reporting Role Screening procedure Signal Transduction Signal Transduction Pathway Small Interfering RNA Staging Stromal Cells T-Cell Leukemia TNFRSF5 gene Technology Testing Transcription Coactivator Transcriptional Regulation base cancer cell cancer gene expression cancer imaging cancer therapy cytokine design flexibility imaging probe improved in vivo inhibitor/antagonist inorganic phosphate mouse model new technology novel optical imaging phosphorothioate ratiometric response small hairpin RNA small molecule technology development technology validation traditional therapy transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Molecular dissection of abnormal regulation of cancer gene expression has revealed many potential targets for cancer therapy. Those targets include the components of normal, as well as abnormal transcription machinery. Proteins involved in regulation of transcription in cancer will attain high priority due to the convergence of many signal transduction pathways at the transcriptional level. New molecular therapies directed to transcriptional targets, including siRNA technology have significant advantages over traditional therapies due to a precision of their interference with target gene expression. While rapid progress in molecular genetics and medicinal chemistry delivers new +attenuators; of gene expression, there is a critical need in developing technologies that enable early and non-invasive assessment of cancer response to these therapies. In particular, enabling imaging technologies that report directly on gene transcription in cancer cells are critically important for both cancer phenotyping and staging, as well as for evaluating new therapies. Optical imaging in the near-infrared range of fluorescence combined with the use of enzyme-specific self- quenched probes has emerged as novel technology of live cancer cell screening. We previously devised a family of fluorescent probes based on synthetic biocompatible carriers of fluorochromes that report on hydrolytic activity in tumor-bearing animals. Recently, we developed new chemistry for generating asymmetrical as well symmetrical oligonucleotide molecular reporter probes (ODMR) designed to sense interactions with pleiotropic and evolutionally conserved components of transcriptional factor nuclear factor NFkappaB (NF-?B). NF-?B plays one of the key roles in tumor progression by regulating expression of cell adhesion, antiapoptotic and cytokine responsive genes in cancer and stromal cells in tumors. We recently tested novel synthetic approaches for introducing hydrophilic, non-interfering linkers into ?B-box sequences for covalent binding of fluorochromes to these probes to any internucleoside phosphate. We propose to develop ODMR technology that will be essential for further advancement of in vivo imaging of cancer-related target transcription activators.

描述（由申请人提供）：对癌症基因表达异常调节的分子解剖揭示了许多癌症治疗的潜在靶点。这些目标包括正常和异常转录机制的组成部分。由于许多信号转导途径在转录水平的会聚，参与癌症转录调控的蛋白质将获得高度优先。针对转录靶点的新分子疗法，包括siRNA技术，由于其干扰靶基因表达的精确性，与传统疗法相比具有显著优势。虽然分子遗传学和药物化学的快速发展提供了新的基因表达的衰减剂，但迫切需要开发能够早期和非侵入性评估癌症对这些疗法的反应的技术。特别是，能够直接报告癌细胞中基因转录的成像技术对于癌症表型和分期以及评估新疗法都至关重要。在荧光的近红外范围内的光学成像结合使用酶特异性自猝灭探针已经成为活癌细胞筛选的新技术。我们以前设计了一个家庭的荧光探针的基础上合成的生物相容性载体的荧光染料，报告在荷瘤动物的水解活性。最近，我们开发了新的化学产生不对称以及对称的寡核苷酸分子报告探针（ODMR）的设计感与多效性和进化保守的转录因子核因子NF κ B（NF-？B）。NF-？B通过调节肿瘤和肿瘤基质细胞中细胞粘附、抗凋亡和细胞因子应答基因的表达在肿瘤进展中起关键作用之一。我们最近测试了新的合成方法引入亲水性，非干扰性连接到？用于荧光染料与这些探针共价结合至任何核苷间磷酸的B盒序列。我们建议开发ODMR技术，这对于进一步推进癌症相关靶转录激活因子的体内成像至关重要。