Defining the Essential Determinants of Prostate Cancer Differentiation States

定义前列腺癌分化状态的基本决定因素

• 批准号: 10004587
• 负责人: Jung Wook Park
• 金额: $ 24.9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004587
• 关键词: AKT1 gene; Address; Adenocarcinoma; Affect; Androgens; Area; Automobile Driving; Award; Binding; Biochemistry; Bioinformatics; Biological Assay; California; Cancer Biology; Cancer Patient; Cell Line; Chairperson; Chromatin; Clinical; Computational Biology; Data; Data Set; Detection; Development; Disease Progression; Disease model; Engineering; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Evolution; Expression Library; Face; Faculty; Future; Genes; Genetic Engineering; Genetic Transcription; Genitourinary system; Goals; High-Throughput Nucleotide Sequencing; Histologic; Human; Investigation; Knowledge; Laboratories; Los Angeles; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Mentors; Metastatic Prostate Cancer; Methodology; Methods; Modeling; Molecular; Neurosecretory Systems; Oncogenic; Operative Surgical Procedures; Organ; Organoids; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacology; Phase; Phenotype; Positioning Attribute; Pre-Clinical Model; Process; Prostate; Prostate Adenocarcinoma; Public Health; Publishing; Radiation therapy; Recurrence; Research; Research Proposals; Resistance; Role; Scientist; Stimulus; Systems Biology; Techniques; Technology; Therapeutic; Time; Training; Translating; Translations; Transposase; Universities; Variant; Woman; advanced prostate cancer; androgen deprivation therapy; anticancer research; c-myc Genes; cDNA Expression; cancer diagnosis; cancer initiation; cancer subtypes; career; career development; castration resistant prostate cancer; deprivation; differential expression; effective therapy; functional genomics; genetic element; genetically modified cells; high throughput analysis; human disease; human model; improved; induced pluripotent stem cell; insight; mRNA sequencing; men; neuroendocrine differentiation; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; pressure; prevent; professor; prostate cancer cell line; prostate cancer model; relating to nervous system; response; screening; skills; transcription factor; transdifferentiation; tumor; tumor immunology; tumor progression

Project Summary/Abstract My long-term career objective is to be an independent scientist in an academic laboratory. I would like to improve our molecular understanding of cancer initiation and progression and translate these findings to new therapeutic approaches for cancer patients. The K99/R00 Pathway to Independence Award and the proposed research in this application will be instrumental in my professional career development as a scientist as I transition to a faculty position. MENTORING TEAM: During the mentored K99 phase of the award, I will perform the proposed research under the direct guidance of Dr. Owen Witte at the University of California at Los Angeles (UCLA). Dr. Witte is a world-renowned leader in the field of cancer research. His laboratory has developed a unique set of research approaches with human materials to address scientific questions and hypotheses in prostate cancer pathogenesis and cancer immunology. I have assembled an advisory board with a co-mentor and two consultants including Dr. Siavash Kurdistani, Professor in the Department of Biological Chemistry at UCLA and an expert in functional genomics; Dr. Thomas Graeber, Professor in the Department of Molecular & Medical Pharmacology at UCLA and an expert in systems biology; and Dr. Jiaoti Huang, Chairman and Professor in the Department of Pathology at Duke University who is a world expert in genitourinary pathology. I will obtain knowledge and new skills in the areas of functional genomics, computational biology, and translation of basic scientific findings therapeutic strategies for cancer patients. This training will allow me to reach my career goal as a scientist who can significantly contribute to the field of cancer biology and the many men and women who are affected by cancer. RESEARCH: We hypothesize that, under the pressure of current therapies, prostate adenocarcinoma (PrAd) undergoes cellular reprogramming and trans-differentiation to a lethal variant, neuroendocrine prostate cancer (NEPC), and this process is driven by dysregulated transcriptional networks. The goal of this proposal is to define the critical genetic elements required for the progression from PrAd to NEPC. The lack of human prostate cancer models has hampered functional studies investigating the molecular mechanisms by which advanced prostate cancer evolves. To address the hypothesis, we will conduct these aims: Aim 1. I will establish a diverse panel of advanced prostate cancer cell lines derived from the transformation of basal and luminal epithelial cells of origin by defined oncogenic drivers. Aim 2. I will perform integrative next-generation sequencing to define transcription factor networks in cancer differentiation states of advanced prostate cancer. Aim 3. I will functionally define a minimal essential set of transcription factors required to reprogram PrAd to NEPC. In future studies, we will build on the insight gained from these studies to pursue therapeutic approaches to prevent the evolution of lethal NEPC.

项目摘要/摘要 我的长期职业目标是成为学术实验室的独立科学家。我想 提高我们对癌症开始和进展的分子理解，并将这些发现转化为 癌症患者的新治疗方法。 K99/R00独立奖和 该应用程序中的拟议研究将在我作为科学家的职业发展中发挥作用 当我过渡到教师职位时。 指导团队：在指导的K99阶段，我将执行拟议的 在加利福尼亚大学洛杉矶分校（UCLA）的欧文·维特（Owen Witte）博士的直接指导下进行研究。博士 维特（Witte）是癌症研究领域的世界知名领导者。他的实验室已经开发了一套独特的 人类材料的研究方法来解决前列腺癌的科学问题和假设 发病机理和癌症免疫学。我已经与一个顾问组合了一个顾问委员会和两个 顾问Siavash Kurdistani博士，加州大学洛杉矶分校生物化学系教授 功能基因组学专家；分子与医学系教授托马斯·格雷伯（Thomas Graeber）博士 加州大学洛杉矶分校的药理学和系统生物学专家；以及Jiaoti Huang博士，董事长兼教授 杜克大学病理学系，他是泌尿生殖器病理学的世界专家。我会得到 功能基因组学，计算生物学领域的知识和新技能以及基本的翻译 癌症患者的科学发现治疗策略。这项培训将使我能够实现自己的职业目标 作为一名科学家，他可以为癌症生物学领域以及许多男人和女人做出重大贡献 受癌症的影响。 研究：我们假设在当前疗法的压力下，前列腺腺癌 （PRAD）经过细胞重编程和反式分化为致命变体的神经内分泌前列腺 癌症（NEPC），此过程由转录网络失调驱动。该提议的目标 是定义从PRAD到NEPC的进展所需的关键遗传因素。缺乏人类 前列腺癌模型阻碍了调查分子机制的功能研究 晚期前列腺癌的发展。为了解决该假设，我们将执行以下目的：目标1。 建立从基础转化和 由定义的致癌驱动器通过定义的原始细胞。目标2。我将执行下一代综合 测序以定义晚期前列腺癌的癌症分化状态中的转录因子网络。 目标3。我将在功能上定义最小的基本基本转录因子，以重新编程为 NEPC。在未来的研究中，我们将基于从这些研究中获得的见解来追求治疗 防止致命NEPC进化的方法。