Neuroendocrine Cancer: Tumor Regulation by PTHrP In Vitro and In Vivo

神经内分泌癌：PTHrP 体外和体内肿瘤调节

• 批准号: 8195905
• 负责人: LEONARD JOHN DEFTOS
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195905
• 关键词: Address; Amino Acids; Animal Model; Area; Behavior; Binding; Biochemical; Biological; Biological Markers; Breast; Chromogranins; Clinical; Complement; Corticotropin; Development; Diagnosis; Diagnostic; Engineering; Family; Functional disorder; Funding; Generations; Growth; Health; Human; Image; Imaging Techniques; Immunoassay; Immunocompromised Host; Immunohistochemistry; Implant; In Vitro; Knowledge; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Medical; Methodology; Methods; Modeling; Molecular; Molecular Biology; Monitor; Multiple Myeloma; Mus; Neurosecretory Systems; Oncogene Proteins; Pathway interactions; Patients; Peptides; Pro-Opiomelanocortin; Procedures; Process; Progress Reports; Property; Prostate; Protein Isoforms; Protein Overexpression; Publications; Regulation; Research; Role; Site; Skeleton; Therapeutic; Translating; Veterans; base; beta-Endorphin; bone; cancer cell; clinical application; clinical effect; immunoaffinity chromatography; in vivo; novel; parathyroid hormone-related protein; polypeptide; progastrin; proglucagon; prohormone; protein expression; public health relevance; research study; skeletal; therapeutic target; tumor; tumor progression; tumorigenesis

Project Summary/Abstract: It is our overall Hypothesis that PTHrP (parathyroid hormone related protein) overexpression in prostate cancer is characterized by the generation of novel, cancer-specific peptides from the three native isoforms of this oncoprotein and that these novel peptides can regulate tumorigenesis and the growth and progression of prostate cancer, especially in the skeleton. Our overall Aim is to identify these peptides and their effects on growth-regulation and tumor progression in order to fully understand the pathobiology of this malignancy. Specific Aim 1. To identify and fully characterize the PTHrP peptides that are derived from the native PTHrP polypeptides in prostate cancer. We shall identify and characterize the PTHrP peptides produced by prostate cancers. This will be accomplished by a multifaceted approach that includes (a) immunochemical procedures like immunoaffinity chromatography, multi-site immunoassays, and immunohistochemistry, including Westerns and (b) biochemical procedures based on mass spectrometry (MS). These methods will be complemented by additional molecular studies of PTHrP. Summary of Expected Results: We expect to identify prostate-specific peptides of PTHrP that mediate effects on growth- and proliferation-related aspects of prostate cancer. In addition to PTHrP's classical peptides, we expect to discover new peptides that can exert their molecular action though novel molecular pathways. Specific Aim 2. To determine how these PTHrP-processed peptides regulate prostate cancer progression in skeletal and other sites. This aim will be accomplished in immunocompromised mice by peptide treatment and by directly implanting into bone and other sites prostate cancer cells that have been genetically engineered for PTHrP expression to respectively manifest the growth regulatory effects of PTHrP and its peptides. Novel imaging procedures will be used to monitor tumor behavior. These models will allow us to study PTHrP's respective effects and molecular interactions that mediate in vivo progression of prostate cancer. Summary of Expected Results: We expect to identify PTHrP peptides that regulate the respective progression, both skeletal and non-skeletal, of prostate cancer in our animal model for this tumor. We expect to inform and focus these in vivo studies based on the corresponding in vitro studies of Aim 1 as well as our Preliminary Results in this area. We expect to identify and elucidate the growth- regulatory domains of PTHrP and its derived peptides in vivo and to thus facilitate exploitation of these mechanisms for the development of diagnostic and therapeutic targets for the tumor.

项目摘要/摘要： 我们的总体假设是PTHRP（甲状旁腺激素相关蛋白）过表达 前列腺癌的特征是三种新颖的，新颖的癌症特异性肽 这种癌蛋白的天然同工型，这些新型肽可以调节肿瘤发生和 前列腺癌的生长和进展，尤其是在骨骼中。我们的总体目的是确定 这些肽及其对生长调节和肿瘤进展的影响，以便完全 了解这种恶性肿瘤的病理学。 特定目的1。确定并充分表征从pTHRP肽 前列腺癌中的天然PTHRP多肽。我们将识别并表征PTHRP 前列腺癌产生的肽。这将通过一种多方面的方法来完成 包括（a）免疫化学程序，例如免疫亲和力色谱，多站点 免疫测定和免疫组织化学，包括西方和（b）生化程序 基于质谱法（MS）。这些方法将由其他分子补充 PTHRP的研究。 预期结果的摘要：我们期望确定PTHRP的前列腺特异性肽 介导对前列腺癌生长和增殖相关方面的影响。除了PTHRP 经典的肽，我们希望发现可以发挥其分子作用的新肽 新型分子途径。 具体目标2。确定这些PTHRP加工的肽如何调节前列腺癌 骨骼和其他部位的进展。这个目标将在免疫功能低下 小鼠通过肽处理，直接植入骨骼和其他部位前列腺癌细胞 已针对PTHRP表达进行了基因设计，以分别表现出生长 PTHRP及其肽的调节作用。新型成像程序将用于监测肿瘤 行为。这些模型将使我们能够研究PTHRP的各自效果和分子相互作用 介导前列腺癌的体内进展。 预期结果的摘要：我们期望识别调节相应的PTHRP肽 在该肿瘤的动物模型中，前列腺癌的骨骼和非骨骼的进展。我们 希望根据相应的AIM 1的体外研究来告知和重点这些体内研究 以及我们在该领域的初步结果。我们希望确定并阐明增长 PTHRP的调节域及其在体内衍生的肽，从而促进 这些用于开发肿瘤诊断和治疗靶标的机制。