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（由适用提供）：我们研究人类怀孕X受体（HPXR）和本构雄烷受体（HCAR）的调节及其在药物处置中的作用。 HPXR和HCAR：1）都是由许多结构上不同化学物质调节的核受体，可以直接通过受体结合或通过信号传导串扰来调节。 2）转录调节药物代谢酶和转运蛋白，以控制异种生物处置和内向生物稳态； 3）不仅在药物作用中，而且在人类疾病（例如糖尿病和癌症）的发展中实施； 4）与类维生素X受体形成异二聚体，以结合其靶基因的启动子，这可能是受体或重叠的独特的； 5）受共激活因子和核压力的影响；和6）相似的互动或与各种调节伙伴（包括化学物质，DNA元素，蛋白质和microRNA）的不同方式不同。我们对HPXR和HCAR调节和功能的总体理解中仍然存在一些关键差距。首先，HPXR和HCAR不仅调节药物代谢，而且还与其他信号分子相互作用，受其调节或受其调节。尽管进步持续，但我们缺乏与其调节器的HPXR和HCAR相互作用以及通过这些相互作用的调节和调节的完整图片。其次，需要进行系统的努力来开发化学工具以详细阐述HPXR和HCAR调节。我们的两个长期目标是全面研究HPXR和HCAR的调节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调节及其在预防药物毒性和改善生物可用性方面的潜在应用。我们通过发现调节HPXR和HCAR的机制，包括蛋白质 - 蛋白质相互作用，翻译后修饰和翻译后调节（microRNAS），以及开发新型的HPXR拮抗剂SPA70，HCAR逆抗激动剂的辛酸固醇和类似物。我们将在资金期间面临3个挑战：（1）说明HPXR和HCAR如何通过检查SPA70在多大程度上阻止药物毒性和CINPA1降低耐药性并确定潜在机制来调节药物毒性和抵抗。（2）通过与拮抗剂（SPA70）（SPA70）和抗激动剂（CINPA1）获得HPXR的共晶结构并进行结构官能分析，定义了负责HPXR拮抗剂和HCAR反向激动剂作用的基本机制。（3）更好地理解HPXR和HCAR蛋白 - 蛋白质相互作用网络以及相互调节效应，首先检查了基因毒性和异种生物毒素反应途径之间的信号传导如何减少遗传毒性应激的效果。总之，我们的发现不仅将对HPXR和HCAR的调节提供更广泛的理解，以及它们如何控制人体对异生元和内生元的反应，还提供HPXR和HCAR的新型调节剂，以进一步询问其广泛的细胞功能，以及用于预防药物毒性毒性和改善药物的疗法。