MicroRNAs in Advanced Prostate Cancer: A miR-21 model

晚期前列腺癌中的 MicroRNA：miR-21 模型

基本信息

批准号：
7984291
负责人：
SHAWN LUPOLD
金额：
$ 34.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7984291
关键词：
Accounting Address Advanced Development American Androgen Receptor Apoptotic Applications Grants Area Biological Assay Cancer Model Castration Communities Complementary DNA Diagnosis Disease Disease Outcome Distant Metastasis Employee Strikes Fluorescent in Situ Hybridization Future Gene Dosage Gene Expression Gene Expression Regulation Genes Goals Growth Health Human Immunohistochemistry In Situ Hybridization Knowledge Light Luciferases Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating MicroRNAs Modeling Neoplasm Metastasis Oncogenes Oncogenic PC3 cell line Pathway interactions Patients Post-Transcriptional Regulation Primer Extension Prognostic Marker Promoter Regions Prostate Radical Prostatectomy Recurrence Regulation Regulator Genes Reporter Research Resistance Role Series Signal Pathway Small Interfering RNA Specimen Systemic Therapy Terminal Disease Testing Tissue Microarray Tissues Transcript United States Western Blotting advanced disease human tissue innovation male men novel outcome forecast promoter public health relevance tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Advanced prostate cancer is an incurable and terminal disease which is characterized by metastasis and castration resistance. The mechanisms of progression to this advanced state are largely unknown. Our long term goal is to identify and characterize pathways which cause this lethal form of prostate cancer. We believe that novel discoveries in this focused area will have significantly impact on the prognosis and treatment of prostate cancer. MicroRNAs are a new class of regulatory molecules which control cellular pathways through post-transcriptional mechanisms. We have identified miR-21 as an Androgen-Receptor-regulated and oncogenic microRNA which is elevated in human prostate cancer. Importantly, miR-21 is sufficient to drive castration resistant tumor growth. In light of these discoveries, and the existing knowledge of miR-21 in other malignancies, we hypothesize that the miR-21 gene locus contributes to the development of advanced prostate cancer. The overall objective of this proposal are to (i) characterize the mechanisms of elevated miR-21 gene expression in human prostate cancer, (ii) to elucidate the pathways utilized by the miR-21 gene locus to promote cancer progression, and to compare miR-21 gene copy number and expression between human prostate cancers which have either been cured by primary therapy or recurred, progressed to metastasis, or castration resistance. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is a health problem of major significance in the United States. PCa strikes over 180,000 American men each year and accounts for approximately 10% of male cancer related deaths1. Despite an escalating research effort, there have been little to no advances in the treatment of metastatic and Castration Resistant Prostate Cancer (CRPC). Moreover, approximately 1/3rd of mean will recur following primary therapy2. Nonetheless, many men diagnosed with PCa will never develop the lethal or even symptomatic form of the disease within their lifetime3. Therefore, there are two major deficiencies in the current management of PCa: (1) Systemic Therapy - the lack of a successful therapy for CRPC and (2) Prognosis - the inability to consistently predict which cancers will progress. This grant application addresses these deficiencies by proposing studies of a novel pathway in CRPC and correlating genes in this pathway with disease recurrence and progression.

描述（由申请人提供）：晚期前列腺癌是一种无法治愈的终末疾病，其特征是转移和cast割耐药性。发展到该先进状态的机制在很大程度上是未知的。我们的长期目标是识别和表征导致这种致命形式前列腺癌的途径。我们认为，在这个重点区域中的新发现将对前列腺癌的预后和治疗产生重大影响。 microRNA是一类新的调节分子，通过转录后机制来控制细胞途径。我们已经将miR-21确定为雄激素受体调节的和致癌的microRNA，在人类前列腺癌中升高。重要的是，miR-21足以驱动耐castration抑制肿瘤的生长。鉴于这些发现以及在其他恶性肿瘤中对miR-21的现有知识，我们假设miR-21基因座有助于晚期前列腺癌的发展。该建议的总体目的是（i）表征人类前列腺癌中miR-21基因表达升高的机制，（ii）阐明miR-21基因座利用的途径以促进癌症进展，并比较miR -21基因拷贝数和人类前列腺癌之间的表达，已通过初级治疗或重复治疗，发展为转移或cast割耐药性。公共卫生相关性：前列腺癌（PCA）是美国具有重要意义的健康问题。 PCA每年罢工超过18万名美国男性，约占男性癌症相关死亡的10％。尽管研究工作不断提高，但在抗转移性和cast割前列腺癌（CRPC）的治疗方面几乎没有任何进展。此外，在初级治疗后，大约1/3平均值将复发2。尽管如此，许多被诊断为PCA的男性永远不会在其一生中发展出疾病的致命形式甚至症状形式3。因此，PCA当前管理中有两个主要缺陷：（1）全身治疗 - 缺乏CRPC和（2）预后的成功疗法 - 无法持续预测哪些癌症会进展。该赠款的应用通过提出对CRPC中新途径的研究来解决这些缺陷，并将该途径中的基因与疾病复发和进展相关联。