Novel Bioconjugates as Probes of Estrogen Receptors

作为雌激素受体探针的新型生物共轭物

• 批准号: 7410036
• 负责人: ROSS V WEATHERMAN
• 金额: $ 26.37万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7410036
• 关键词: 4-Hydroxy-Tamoxifen; Affect; Apoptosis; Area; Behavior; Binding; Biological; Biological Assay; Cell Line; Cell Nucleus; Cell membrane; Cells; Chemistry; Class; Contraceptive methods; Cyclic AMP; Cytoplasm; Drug Delivery Systems; Drug usage; Endoplasmic Reticulum; Estradiol; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exhibits; Fulvestrant; G-Protein-Coupled Receptors; Genetic Transcription; Goals; Immunoblotting; In Vitro; Label; Length; Ligands; Localized; Measures; Mediating; Membrane; Menopause; Microscopy; Modeling; Molecular; Numbers; Pattern; Pharmaceutical Preparations; Play; Polymers; Positioning Attribute; Property; Range; Reporter; Research; Resistance development; Role; Signal Pathway; Signal Transduction; Solubility; Structure; Structure-Activity Relationship; Tamoxifen; Testing; Tetrazoles; Time; Tissues; analog; base; density; fluorophore; malignant breast neoplasm; mutant; nanocrystal; nanoparticle; novel; polymerization; polymethacrylate; receptor; receptor function; response; scaffold; size; steroid hormone; steroid hormone receptor; uptake

DESCRIPTION (provided by applicant): Estrogen-based drugs are used widely for treatment areas ranging from breast cancer to menopause to contraception, but all of them suffer limitations due to unwanted effects of the drugs in other tissues. The long-term goal of this proposed research is to elucidate the molecular details of estrogen signaling in the context of other signaling pathways in the cell and how crosstalk with these signaling pathways dictate the response profiles of estrogen-mimicking drugs. Growing evidence suggests that steroid hormones can elicit responses from receptors located outside of the nucleus. Possible receptors for these responses, which have been noted for all steroid hormones, range from novel classes of membrane-spanning receptors to G-protein coupled receptors located on endoplasmic reticulum to different forms of the classic steroid hormone receptor. We hypothesize that targeting estrogen ligands to certain parts of the cell could selectively modulate some of these responses. We propose to carry out several different studies of different types of estrogen-regulated responses focusing on how ligand structure and receptor localization play a role in modulating different types of responses to estrogenic and antiestrogenic compounds. Aim 1 is focused on the synthesis of novel macromolecular conjugates of different estrogen-mimicking analogs that localize to different parts of the cell. We have found that 4-hydroxytamoxifen conjugated to different scaffolds can localize to the nucleus, cytoplasm, or outer plasma membrane. Whether other estrogen ligands can elicit the same pattern of localization will be explored. Aim 2 is focused on investigating how ligand structure and localization affects a number of different estrogen responses. Our previous results support the hypothesis that the structure-activity relationships underlying many of these crosstalk-dependent responses are significantly different than those underlying classic estrogen receptor activity, and Aim 2 will focus on assays looking at a number of diverse responses to estrogen and whether localization of the ligand to certain parts of the cell can also play a role. In aim 3, we propose to investigate whether the properties of the conjugates themselves are responsible for some of their biological effects and explore possible effects of multivalency and conjugation chemistry. Aim 4 will look at the functional actions of the conjugates on the different estrogen receptors and on a number of cellular responses to estrogenic and antiestrogenic compounds.

描述（由申请人提供）：雌激素类药物广泛用于从乳腺癌到绝经到避孕的治疗领域，但由于药物在其他组织中的不良作用，所有这些药物都受到限制。这项拟议研究的长期目标是阐明细胞中其他信号传导途径背景下雌激素信号传导的分子细节，以及与这些信号传导途径的串扰如何决定雌激素模拟药物的反应特征。越来越多的证据表明，类固醇激素可以引起位于细胞核外的受体的反应。这些反应的可能受体，已注意到所有类固醇激素，范围从跨膜受体的新类别的G-蛋白偶联受体位于内质网的不同形式的经典类固醇激素受体。我们假设，靶向雌激素配体的某些部分的细胞可以选择性地调节这些反应。我们建议进行几个不同的研究，不同类型的雌激素调节的反应，重点是如何配体结构和受体定位发挥作用，调节不同类型的反应，雌激素和抗雌激素化合物。目的1是集中于合成定位于细胞不同部位的不同雌激素模拟类似物的新型大分子缀合物。我们已经发现，4-羟基他莫昔芬结合到不同的支架可以定位到细胞核，细胞质，或外质膜。其他雌激素配体是否能引起相同的定位模式将进行探讨。目的2是研究配体结构和定位如何影响一些不同的雌激素反应。我们以前的研究结果支持这一假设，即许多这些串扰依赖性反应的结构-活性关系与经典雌激素受体活性的结构-活性关系显著不同，Aim 2将专注于研究对雌激素的多种反应的测定，以及配体在细胞某些部位的定位是否也可以发挥作用。在目标3中，我们建议研究缀合物本身的性质是否是它们的一些生物学效应的原因，并探索多价性和缀合化学的可能影响。目的4将着眼于不同的雌激素受体和对雌激素和抗雌激素化合物的细胞反应的共轭物的功能作用。