Cytoprotective Autophagy in Bone Metastatic Prostate Cancer

骨转移性前列腺癌中的细胞保护性自噬

基本信息

批准号：
8298867
负责人：
NIKKI A DELK
金额：
$ 11.5万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-08 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298867
关键词：
Address Administrator American Apoptosis Apoptotic Attenuated Autophagocytosis Biological Assay Biology Bone Marrow Cancer Biology Cause of Death Cell Cycle Cell Death Cell Differentiation process Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Coculture Techniques Collaborations Communication Core Facility Data Delaware Dyes Education Elements Environment Equipment Exposure to Faculty Funding Funding Mechanisms Genetic Goals Growth Investigation Malignant neoplasm of prostate Mediating Medical center Mentors Metabolic stress Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Mitotic Modeling Neurons Neurosecretory Systems Paracrine Communication Pathway interactions Phenocopy Phenotype Physiological Positioning Attribute Process Proteins Publishing Radiation Recycling Regulation Research Resistance Resources Rice Role Science Signal Pathway Site Staining method Stains Stromal Cells Texas Tumor Suppression Universities Vesicle abstracting angiogenesis attenuation bone cancer cell cancer health disparity career career development cytotoxic experience inhibition of autophagy killings meetings men mortality outcome forecast paracrine professor response skills skills training tumor tumor growth

项目摘要

Project Summary/Abstract Candidate: My immediate career goals are to obtain the necessary training and skill set required to be competitive for a tenured faculty position and to accumulate data sufficient for an R01 or similar funding mechanism. My long term career goals are to be a tenured, funded cancer biology professor, a mentor, and a science administrator. To this end, the key elements of my career plan are focused on 1) developing my independent research, 2) continuing my technical and research administrative education, 3) honing my communication skills, and 4) gaining more mentoring experience. Environment: I can successfully meet my goals because I have access to state-of-the-art equipment, core facilities, and educational resources at Rice University, the Texas Medical Center, and through a prostate cancer P01 collaboration that includes the University of Delaware, Emory University, and Cedars-Sinai. I also have a team of phenomenal mentors who are leaders in the prostate cancer and cancer health disparities fields. These mentors include my primary mentor, Dr. Mary Farach-Carson, co-mentor, Dr. Leland Chung, and Drs. Nora Navone and Lovell Jones, who have each agreed to provide me with career development guidance. Research: Prostate cancer (PCa) is the second leading cause of death in North American men, where 80% of PCa mortality is due to bone metastasis. PCa tumors can contain neuronal-like neuroendocrine (NE) PCa cells, which correlates with poor prognosis. NE PCa cells are resistant to apoptosis, secrete proteins to induce cell proliferation and angiogenesis, and can de-differentiate to contribute to tumor growth. Our lab recently published data revealing that bone marrow stromal cell (BMSC) paracrine signaling induces apoptosis in co-cultured bone metastatic PCa cells. However, a subpopulation of the bone metastatic PCa cells can avoid cell death and undergo neuroendocrine differentiation (NED). One process that has been shown to mediate cancer cell survival and cell differentiation is autophagy, the homeostatic process of intracellular degradation and recycling. Thus, I propose that autophagy is a cytoprotective mechanism that PCa cells use to survive and undergo NED in the bone marrow stromal microenvironment. To address my hypothesis, I will (1) dissect autophagy regulation in PCa cells exposed to BMSC, (2) demonstrate that autophagy enhances PCa cell survival and promotes NED, and (3) show that autophagy attenuation increases PCa cell death. Autophagy induction and function will be analyzed using immuno-blot and -staining for autophagy markers, such as LC3, and using acidic vesicle dyes, such as monodansylcadaverin. PCa cells will be subjected to genetic and pharmacological autophagy modulation and assayed for cell viability and the NED phenotype. My investigation will identify pathways to attenuate autophagy and redirect bone metastatic PCa cells towards cell death.

项目摘要/摘要候选人：我的直接职业目标是获得必要的培训和技能，以使终身教师职位具有竞争力，并为R01或类似资金机制积累足够的数据。我的长期职业目标是成为终身资助的癌症生物学教授，导师和科学管理员。为此，我的职业计划的关键要素集中在1）发展我的独立研究，2）继续我的技术和研究行政教育，3）磨练我的沟通技巧； 4）获得更多的指导经验。环境：我可以成功实现自己的目标，因为我可以在赖斯大学，得克萨斯州医学中心以及包括特拉华大学，埃默里大学和雪松 - 西奈的前列腺癌P01合作中获得最先进的设备，核心设施和教育资源。我还有一组惊人的导师，他们是前列腺癌和癌症健康差异领域的领导者。这些导师包括我的主要导师，玛丽·法拉赫·卡森（Mary Farach-Carson），同事，钟（Leland Chung）博士和博士。 Nora Navone和Lovell Jones都同意为我提供职业发展指导。研究：前列腺癌（PCA）是北美男性死亡的第二大原因，其中80％的PCA死亡率是由于骨转移引起的。 PCA肿瘤可能包含神经元样神经内分泌（NE）PCA细胞，与预后不良有关。 NE PCA细胞对凋亡具有抗性，分泌蛋白质诱导细胞增殖和血管生成，并可以去分化以促进肿瘤生长。我们的实验室最近发布的数据表明，骨髓基质细胞（BMSC）旁分泌信号传导诱导共培养的骨转移性PCA细胞中凋亡。但是，骨转移性PCA细胞的亚群可以避免细胞死亡并经历神经内分泌分化（NED）。一个已显示可介导癌细胞存活和细胞分化的过程是自噬，这是细胞内降解和回收的稳态过程。因此，我建议自噬是一种细胞保护机制，PCA细胞用来在骨髓基质微环境中生存和经历NED。为了解决我的假设，我将（1）剖析暴露于BMSC的PCA细胞中的自噬调节，（2）证明自噬可增强PCA细胞的存活并促进NED，并且（3）表明自噬衰减会增加PCA细胞死亡。自噬和功能将使用免疫印迹和旋转来分析自噬标记，例如LC3，以及使用酸性囊泡染料（例如单支持者）。 PCA细胞将受到遗传和药理自噬调节的约束，并测定细胞活力和NED表型。我的调查将确定减弱自噬和重定向骨转移性PCA细胞的途径，向细胞死亡。