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Parp Function in Prostate Cancer

Parp 在前列腺癌中的功能

基本信息

批准号：
10582213
负责人：
Bryce Paschal
金额：
$ 46.87万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582213
关键词：
ADP ribosylation Adenosine Diphosphate Ribose Agonist American Amino Acids Androgen Receptor Androgens Animal Model Binding Biochemical Bioinformatics Biological Biological Assay Cause of Death Cell Culture Techniques Cell Line Chemistry Clinical Clinical Trials Communication Complex Cysteine Denmark Dependence Ensure Finland Funding Gene Expression Genes Genetic Transcription Genomics Growth Histones International Ligase Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Massachusetts Mediating Modeling Modification Molecular Molecular Conformation N-terminal Neoplasm Metastasis Netherlands Outcome PARP inhibition PARP9 gene Pathway interactions Peptide Synthesis Phenotype Poly(ADP-ribose) Polymerase Inhibitor Positioning Attribute Pre-Clinical Model Prostate Prostatic Neoplasms Proteins Proteome Reaction Reader Reading Regulation Scientist Signal Transduction Site Specific qualifier value Structure Testing Therapeutic Transcriptional Regulation Transducers Virginia Work Writing Xenograft Model androgen sensitive castration resistant prostate cancer experimental study inhibitor knowledge base men mutant new therapeutic target non-genomic novel novel therapeutics permissiveness prevent prostate cancer cell prostate cancer model prostate carcinogenesis structural biology success synthetic peptide tool transcription factor tumor growth tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY This proposal builds upon our discovery in the previous funding period of a novel pathway in prostate cancer cells that integrates androgen signaling with ADP-ribosylation. The pathway has four key components, the androgen receptor (AR), Parp7, Parp9 and Dtx3L. We found that the pathway involves AR induction of Parp7 and multi-site mono-ADP-ribosylation by Parp7, on cysteines in the AR amino-terminal domain. In this pathway, Parp7 acts as an ADP-ribose writer and Parp9 serves as an ADP-ribose reader, and the outcome of these reactions is androgen- dependent assembly of an AR-Dtx3L/Parp9 complex and regulation of AR activity as a transcription factor. With this knowledge base, we are positioned to tackle important questions on how the pathway drives biological effects in prostate cancer cells, and whether Parp7 is an actionable target in models that include castrate-resistant prostate cancer where there is an unmet clinical need. In Aim 1, we will determine how the AR-Parp7 pathway and mono-ADP- ribosylation regulate tumorigenesis in prostate cancer cells using structure-function experiments that interrogate the contributions of each of the four components. Since AR is the only known Parp7 substrate in prostate cancer cells, we will define the ADP-ribosyl-proteome in prostate cancer cells to identify additional, AR-independent pathways, by which Parp7 regulates prostate cancer cells. In Aim 2 we will determine the molecular basis for ADP-ribose writing and reading on the AR-Parp7 pathway. Parp7 ADP-ribosylation of AR is specific for androgen-bound AR, and we have a strategy in place to determine how the agonist conformation of AR generates sites that are permissive for ADP-ribosylation. AR will be used as a model to study the reader function of Parp9 macrodomains, in particular, the features that are important for selectivity. In Aim 3 we determine the vulnerability of prostate cancer cells to a first-in-class Parp7 inhibitor, and test whether the inhibitor can prostate growth and metastasis. Our study will benefit from significant contributions from a team of national and international scientists with expertise in prostate cancer models, proteome-scale mass spectrometry, synthetic peptide chemistry, Parp structural biology, and implementation of Parp inhibitors. Our overall hypothesis is that androgen signaling transduced through Parp7 regulates both genomic and non-genomic pathways, and that selective blockade of Parp7 will inhibit prostate tumorigenesis. If the hypothesis is correct, our work will identify Parp7 as a new therapeutic target in prostate cancer and expand the toolbox of Parp inhibitor-based treatments.

项目概要该提案建立在我们在上一个资助期间发现的一条新途径的基础上将雄激素信号传导与 ADP-核糖基化整合的前列腺癌细胞。该路径有四个关键成分：雄激素受体 (AR)、Parp7、Parp9 和 Dtx3L。我们发现途径涉及 Parp7 的 AR 诱导和 Parp7 的多位点单 ADP 核糖基化， AR 氨基末端结构域中的半胱氨酸。在此通路中，Parp7 充当 ADP 核糖书写者 Parp9 充当 ADP-核糖阅读器，这些反应的结果是雄激素- AR-Dtx3L/Parp9 复合物的依赖组装和 AR 活性的调节转录因子。有了这个知识库，我们就可以解决重要问题关于该通路如何驱动前列腺癌细胞的生物效应，以及 Parp7 是否是一个包括去势抵抗性前列腺癌在内的模型中的可行目标未满足的临床需求。在目标 1 中，我们将确定 AR-Parp7 途径和 mono-ADP- 使用结构功能实验核糖基化调节前列腺癌细胞的肿瘤发生询问四个组成部分中每个组成部分的贡献。由于 AR 是唯一已知的前列腺癌细胞中的 Parp7 底物，我们将定义前列腺中的 ADP-核糖基-蛋白质组癌细胞识别额外的、不依赖 AR 的途径，Parp7 通过这些途径调节前列腺癌细胞。在目标 2 中，我们将确定 ADP-核糖写入和读取的分子基础 AR-Parp7 通路上。 AR 的 Parp7 ADP 核糖基化对雄激素结合的 AR 具有特异性，我们有一个策略来确定 AR 的激动剂构象如何生成允许 ADP 核糖基化的位点。 AR将用作模型来研究读者 Parp9 宏结构域的功能，特别是对选择性很重要的特征。在目标 3 我们确定前列腺癌细胞对一流 Parp7 抑制剂的脆弱性，并测试该抑制剂是否能使前列腺生长和转移。我们的学习将受益于由具有专业知识的国家和国际科学家团队做出的重大贡献前列腺癌模型、蛋白质组质谱、合成肽化学、Parp 结构生物学和 Parp 抑制剂的实施。我们的总体假设是通过 Parp7 转导的雄激素信号调节基因组和非基因组选择性阻断 Parp7 将抑制前列腺肿瘤发生。如果假设是正确的，我们的工作将确定 Parp7 作为前列腺癌的新治疗靶点并扩展基于 Parp 抑制剂的治疗的工具箱。