Regulation of xenobiotic receptors PXR and CAR: implications in drug disposition

外源性受体 PXR 和 CAR 的调节：对药物处置的影响

基本信息

批准号：
9516642
负责人：
Taosheng Chen
金额：
$ 6.13万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9516642
关键词：
Affect Agonist Binding Biological Availability Cell physiology Cells Chemicals Comprehension Crystallization DNA Development Diabetes Mellitus Drug Sensitization Drug resistance Drug toxicity Elements Enzymes Funding Gene Targeting Genetic Transcription Genotoxic Stress Goals Homeostasis Human Human body Malignant Neoplasms MicroRNAs Nuclear Receptors Pathway interactions Pharmaceutical Preparations Post-Transcriptional Regulation Post-Translational Protein Processing Proteins RXR Regulation Role Signal Transduction Signaling Molecule Structure Therapeutic Toxic effect Treatment Efficacy Treatment Failure Xenobiotics analog chemotherapeutic agent constitutive androstane receptor drug metabolism genotoxicity human disease improved novel pregnane X receptor prevent promoter protein protein interaction public health relevance receptor receptor binding response tool

项目摘要

DESCRIPTION (provided by applicant): We study regulation of the human pregnane X receptor (hPXR) and constitutive androstane receptor (hCAR) and their roles in drug disposition. Both hPXR and hCAR: 1) are nuclear receptors modulated by many structurally diverse chemicals, either directly via receptor binding or indirectly via signaling cross-talk; 2) transcriptionally regulate drug metabolizing enzymes and transporters to control xenobiotic disposition and endobiotic homeostasis; 3) are implicated not only in drug effects but also in the development of human diseases, such as diabetes and cancer; 4)form heterodimers with retinoid X receptor to bind the promoters of their target genes, which may be unique to a receptor or overlap; 5) are affected by coactivators and corepressors; and 6) interact similarly or differently with various regulatory partners, including chemicals, DNA elements, proteins, and microRNAs. Several key gaps remain in our overall understanding of hPXR and hCAR regulation and function. First, hPXR and hCAR not only regulate drug metabolism but also interact with other signaling molecules, regulating or being regulated by them. Despite ongoing progress, we lack a complete picture of hPXR and hCAR interactions with their regulators, and of the regulation by and regulation of these interactions. Second, a systematic effort is needed to develop chemical tools to dissect hPXR and hCAR regulation in detail. Our two long-term goals are to comprehensively examine the regulation of hPXR and hCAR and its implications for drug disposition and human diseases, and to develop chemical tools to elucidate hPXR and hCAR regulation and its potential application for preventing drug toxicity and improving bioavailability. We have advanced toward these goals by discovering mechanisms that regulate hPXR and hCAR, including protein-protein interactions, post-translational modification and post-transcriptional regulation (microRNAs), and by developing the novel hPXR antagonist SPA70, the hCAR inverse agonist CINPA1, and their analogs. We will meet 3 challenges during the funding period: (1) Illustrate how hPXR and hCAR regulate drug toxicity and resistance by examining to what extent SPA70 prevents drug toxicity and CINPA1 reduces drug resistance and determining the underlying mechanisms. (2) Define the fundamental mechanism responsible for the action of hPXR antagonists and hCAR inverse agonists by obtaining the co-crystal structures of hPXR with antagonist (SPA70) and hCAR with inverse agonist (CINPA1) and carrying out structural-functional analysis. (3) Better understand hPXR and hCAR protein-protein interaction networks and reciprocal regulatory effects, starting by examining how signaling cross-talk between genotoxic- and xenobiotic-responsive pathways reduces the effect of genotoxic stress. Together, our findings will provide not only a broader comprehension of the regulation of hPXR and hCAR and how they control the human body's response to xenobiotic s and endobiotics, but also novel modulators of hPXR and hCAR for further interrogating their broad cellular function, and as leads for therapies to prevent drug toxicity and improve drug bioavailability.

描述（由申请人提供）：我们研究人类孕烷 X 受体 (hPXR) 和组成型雄甾烷受体 (hCAR) 的调节及其在药物处置中的作用：1) 是由许多结构不同的化学物质调节的核受体，直接通过受体结合或间接通过信号串扰；2) 转录调节药物代谢酶和转运蛋白以控制外源物处置和内生素稳态； 3）不仅与药物作用有关，还与人类疾病的发展有关，例如糖尿病和癌症；4）与类视黄醇X受体形成异二聚体以结合其靶基因的启动子，该启动子可能是受体特有的或重叠的; 5) 受到共激活剂和辅阻遏物的影响；并且 6) 相互作用相似或我们对 hPXR 和 hCAR 调控和功能的总体理解仍存在一些差异，其中包括化学物质、DNA 元件、蛋白质和 microRNA。首先，hPXR 和 hCAR 不仅调节药物代谢，还与其他信号分子相互作用。尽管不断取得进展，但我们缺乏 hPXR 和 hCAR 与其调节剂的相互作用以及这些相互作用的调节和调节的完整了解。我们的两个长期目标是全面研究 hPXR 和 hCAR 的调控及其对药物处置和人类疾病的影响，并开发化学工具来阐明 hPXR 和 hCAR 的调控及其潜在应用。通过发现调节 hPXR 和 hCAR 的机制，包括蛋白质-蛋白质相互作用、翻译后修饰和转录后调节，我们已经朝着这些目标迈出了一步。（microRNA），并通过开发新型 hPXR 拮抗剂 SPA70、hCAR 反向激动剂 CINPA1 及其类似物，我们将在资助期间遇到 3 个挑战：（1）通过检查什么来说明 hPXR 和 hCAR 如何调节药物毒性和耐药性。 SPA70 可以预防药物毒性，CINPA1 可以降低耐药性并确定潜在机制 (2) 定义 hPXR 拮抗剂作用的基本机制和hCAR反向激动剂通过获得hPXR与拮抗剂（SPA70）和hCAR与反向激动剂（CINPA1）的共晶结构并进行结构功能分析（3）更好地了解hPXR和hCAR蛋白质-蛋白质相互作用网络和相互调节作用。，首先检查基因毒性和异生素响应途径之间的信号串扰如何降低基因毒性应激的影响，我们的研究结果将提供不一样的结果。不仅可以更广泛地理解 hPXR 和 hCAR 的调节以及它们如何控制人体对异生素和内生素的反应，而且还可以作为 hPXR 和 hCAR 的新型调节剂，以进一步探究其广泛的细胞功能，并作为预防药物毒性和治疗的先导疗法。提高药物的生物利用度。