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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.

项目摘要这项提议建立在我们在前一个资助期发现的一种新途径的基础上，前列腺癌细胞整合雄激素信号与ADP-核糖基化。该路径具有四个关键成分，雄激素受体（AR），Parp 7，Parp 9和Dtx 3L。我们发现途径涉及Parp 7的AR诱导和Parp 7的多位点单ADP核糖基化， AR氨基末端结构域中的半胱氨酸。在这条通路中，Parp 7作为ADP-核糖书写器发挥作用 Parp 9作为ADP-核糖阅读器，这些反应的结果是雄激素- AR-Dtx 3L/Parp 9复合物的依赖性组装和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的问题，关于该途径如何驱动前列腺癌细胞中的生物学效应，以及Parp 7是否是一种模型中的可操作目标，包括去势抵抗性前列腺癌，其中存在未满足的临床需求。在目标1中，我们将确定AR-Parp 7通路和单-ADP-1如何与AR-Parp 7通路结合。核糖基化对前列腺癌细胞肿瘤发生的调控作用询问四个组成部分中每一个的贡献。由于AR是唯一已知的在前列腺癌细胞中的Parp 7底物，我们将定义前列腺中的ADP-核糖基-蛋白质组癌细胞，以确定额外的，AR-独立的途径，其中Parp 7调节前列腺癌细胞在目标2中，我们将确定ADP-核糖写入和阅读的分子基础在AR-Parp 7通路上。AR的Parp 7 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的激动剂构象如何产生允许ADP核糖基化的位点。AR将被用作研究读者的模型 Parp 9宏结构域的功能，特别是对选择性重要的特征。在目的3我们确定前列腺癌细胞对第一类Parp 7抑制剂的脆弱性，并检测该抑制剂是否能抑制前列腺生长和转移。我们的研究将受益于具有以下专长的国家和国际科学家团队的重大贡献：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Parp 7转导的雄激素信号传导调节基因组和非基因组 Par p7的选择性阻断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Parp 7作为前列腺癌的新治疗靶点并扩展基于Parp通道的治疗工具箱。