Parp Function in Prostate Cancer

Parp 在前列腺癌中的功能

基本信息

批准号：
10091413
负责人：
Bryce Paschal
金额：
$ 35.43万
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091413
关键词：
ADP Receptors ADP Ribose Transferases Address American Androgen Receptor Androgens Area BRCA1 gene BRCA2 gene Binding Sites Biochemical Biological Assay Biology Castration Catalytic Domain Cause of Death Cells ChIP-seq Clinical Communication Complex DNA DNA Damage DNA Repair DNA Repair Pathway Data Enzymes Family member Gene Expression Genetic Transcription Genome Genome Stability Genomics Genotype Goals Ionizing radiation Ligands Maintenance Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Mono(ADP-Ribose) Transferases Multienzyme Complexes Neoplasm Metastasis PARP9 gene Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phosphorylation Poly Adenosine Diphosphate Ribose Prostate Prostate Cancer therapy Proteins Reaction Repair Complex Resistance Signal Transduction Site Therapeutic Topoisomerase II Work androgen deprivation therapy androgen sensitive base defined contribution design ds-DNA experimental study improved improved outcome inhibitor/antagonist insight men novel personalized medicine prostate cancer cell prostate carcinogenesis recruit repair function repaired response therapy resistant transcription factor tumor growth tumorigenesis ubiquitin ligase ubiquitin-protein ligase

项目摘要

ABSTRACT The androgen receptor (AR) makes profound contributions to the biology of prostate cancer cells, principally through its function as a ligand-regulated transcription factor. As such, therapeutic approaches to prostate cancer are typically designed to deplete or compete with endogenous androgens with the goal of reducing the transcription function of AR. This proposal addresses a relatively unexplored area of AR action, which is how it generates and responds to DNA damage. In brief, we have developed a large set of preliminary data that shows AR is part of an signaling axis that is initiated by androgen, requires inputs from the DNA damage and repair machinery, and results in assembly of a DNA repair complex. We found that one of the key enzymes in this pathway is Parp7, a mono-ADP-ribosytransferase for which little is known. In Aim1 we will determine how Parp7 is regulated by androgen and DNA damage signaling in prostate cancer cells. In Aim2 we will determine how Parp7 regulates the assembly and DNA repair function of an E3 ubiquitin ligase/ADP-ribosyltransferase complex. In Aim3 we will define the contribution of the signaling axis to genome maintenance, tumorigenesis, and therapy response. The enzymes that mediate DNA damage response and repair reactions have emerged as actionable targets in malignancies including prostate cancer. Inhibitors to the poly-ADP-ribosyltransferase family member, Parp1, improve outcomes in therapy- resistant prostate cancer, though the benefit depends on the status of the DNA repair machinery, notably the BRCA1/BRCA2 genotype. Thus, while the clinical findings provide proof-of-principle for targeting DNA repair pathways, they also underscore the importance of defining and incorporating biochemical and genomic context into treatment rationale. In summary, our studies will define the biochemical relationships between androgen signaling and DNA damage and repair pathways, and help provide new insights into the vulnerabilities of prostate cancer cells.

抽象的雄激素受体（AR）对前列腺生物学做出了深远的贡献癌细胞，主要是通过其作为配体调节转录因子的功能。作为因此，前列腺癌的治疗方法通常旨在耗尽或与内源性雄激素竞争，目的是降低转录功能的 AR。该提案解决了 AR 行动的一个相对未被探索的领域，这就是它的方式产生并响应 DNA 损伤。简而言之，我们开发了一大套初步数据显示 AR 是由雄激素启动的信号轴的一部分，需要来自 DNA 损伤和修复机制的输入，并导致组装 DNA修复复合物。我们发现该途径中的关键酶之一是Parp7，一种人们知之甚少的单 ADP 核糖转移酶。在目标 1 中，我们将确定如何 Parp7 受前列腺癌细胞中雄激素和 DNA 损伤信号传导的调节。在 Aim2我们将确定Parp7如何调节DNA组装和DNA修复功能 E3 泛素连接酶/ADP-核糖基转移酶复合物。在 Aim3 中我们将定义信号轴对基因组维护、肿瘤发生和治疗的贡献回复。介导 DNA 损伤反应和修复反应的酶具有成为包括前列腺癌在内的恶性肿瘤的可行目标。抑制剂聚 ADP 核糖基转移酶家族成员 Parp1 可改善治疗结果耐药性前列腺癌，尽管益处取决于 DNA 修复的状态机制，特别是 BRCA1/BRCA2 基因型。因此，虽然临床发现为靶向 DNA 修复途径提供了原理验证，他们还强调了定义生化和基因组背景并将其纳入其中的重要性治疗原理。总之，我们的研究将定义生化关系雄激素信号传导与 DNA 损伤和修复途径之间的关系，并帮助提供对前列腺癌细胞脆弱性的新见解。