CITED1 nuclear localization and its role in Wilms' tumor pathogenesis

CITED1核定位及其在肾母细胞瘤发病机制中的作用

• 批准号: 7687380
• 负责人: Harold Newton Lovvorn
• 金额: $ 12.73万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687380
• 关键词: Award; Behavior; Binding; Biochemistry; Biological; Biology; C-terminal; Cell Line; Cell Nucleus; Cells; Child; Childhood; Cytoplasm; Cytosol; Data; Developmental Biology; Differentiation Therapy; Disease; Down-Regulation; Embryo; Epithelial; Foundations; Fractionation; Future; Gene Silencing; Grant; Human; In Vitro; Investigation; Kidney; Knowledge; Lead; Learning; Length; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Mentors; Mesenchyme; Modification; Molecular Chaperones; Nephroblastoma; Nuclear; Nuclear Export; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Phase; Population; Post-Translational Protein Processing; Primary Neoplasm; Proteins; Rattus; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; Sucrose; Supervision; Techniques; Testing; Time; Training; Training Programs; Transactivation; Transcriptional Activation; Tumor Biology; Tumor Cell Line; Undifferentiated; Universities; Work; blastema; cancer cell; career; epithelial to mesenchymal transition; in vivo; multidisciplinary; mutant; neoplastic cell; nucleocytoplasmic transport; overexpression; postnatal human; programs; protein complex; protein protein interaction; response; skills; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): This Pathway to Independence Award outlines an initial two-year mentored training program followed by a three-year independent phase to expedite the transition to scientific independence for Dr. Lovvorn. In the initial mentored phase, Dr. Lovvorn proposes to expand his scientific skills and knowledge in the fields of Cancer and Developmental Biology through a multidisciplinary program under the supervision of Dr. Mark de Caestecker, a highly productive principle investigator and respected mentor at Vanderbilt University. With the endorsement of his Department Chair, Dr. Lovvorn currently is practicing a work effort formula that affords 75% of his weekday time for research purposes. The research plan detailed herein will provide Dr. Lovvorn with rigorous training in basic biochemistry techniques to test the functional significance of and mechanisms regulating nucleocytoplasmic shuttling of the transcriptional co-factor CITED1 in Wilms' tumor. Under Dr. de Caestecker's guidance, Dr. Lovvorn has shown that expression of,CITED1, normally active in the developing but absent in the mature kidney, persists in both human and rat Wilms' tumors. He also has shown that the subcellular localization of CITED1 shifts from the cytoplasm in metanephric mesenchyme to the nucleus of malignant blastema, and that increasing levels of CITED1 expression in primary human Wilms' tumors correlate with advanced stages of disease. Dr. Lovvorn proposes two hypotheses from these observations: 1. CITED1 nuclear localization facilitates Wilms' tumor pathogenesis, and 2. Nucleocytoplasmic shuttling of CITED1 is dysregulated in Wilms' tumorigenesis. In his initial aim, Dr. Lovvorn will test the pathogenic significance of restricting CITED1 to the nucleus of Wilms1 tumor cells. He will generate two Wilms' tumor cell lines that misexpress either a predominantly cytosolic or nuclear fraction of CITED1 in the human Wilms' tumor cell line, WIT49, and will assess the effects of these manipulations on Wilms' tumor biology. In his second aim, Dr. Loworn, using mass spectrometry, will identify CITED1 binding partners that are specific to either subcellular compartment. These data will facilitate identification of CITED1 modifications and mechanisms regulating its nuclear retention in Wilms' tumor blastema. These studies will provide a framework not only to understand altered CITED1 nucleocytoplasmic shuttling in, and its contributions to, Wilms' tumor pathogenesis, but also the necessary training to pursue future independent investigation.

描述（由申请人提供）：独立奖的这一途径概述了最初的为期两年的指导培训计划，然后进行了为期三年的独立阶段，以加快洛夫沃博士的过渡到科学独立性的过渡。在最初的指导阶段，Lovvorn博士建议通过在范德比尔特大学（Vanderbilt University）的高效原则研究者和受人尊敬的导师Mark de Caestecker博士的监督下，通过多学科生物学领域扩大他在癌症和发育生物学领域的科学技能和知识。在他的部门主席的认可下，洛夫沃恩博士目前正在练习一个工作努力公式，该公式可为研究目的提供75％的工作日时间。本文详细的研究计划将为Lovvorn博士提供基本生物化学技术的严格培训，以测试调节Wilms肿瘤中转录coctortional Coctor cotctor的核质细胞质穿梭的功能重要性和机制。在De Caestecker博士的指导下，Lovvorn博士表明，人们通常在发展中的表达，但在成熟的肾脏中不存在于人类和Rat Wilms的肿瘤中。他还表明，引用1的亚细胞定位从元素间充质中的细胞质转移到恶性胚芽的细胞核，并且在原发性人类威尔姆斯肿瘤中，引用1表达的水平增加与晚期疾病阶段相关。 Lovvorn博士提出了从这些观察结果中提出的两个假设：1。引用的1个核定位促进了Wilms的肿瘤发病机理，2。在Wilms的肿瘤发生中，引用的1的核质梭状造影。在最初的目标中，洛夫沃恩博士将测试将引用1限制为Wilms1肿瘤细胞核的致病意义。他将产生两种Wilms的肿瘤细胞系，这些细胞系在人Wilms的肿瘤细胞系WIT49中，主要是胞质或核比例，并将评估这些操纵对Wilms肿瘤生物学的影响。在他的第二个目标中，Loworn博士使用质谱法，将识别特定于任何一个亚细胞室的引用的结合伙伴。这些数据将有助于鉴定引用的1修改和调节其在Wilms肿瘤胚芽中的核保留率的机制。这些研究将提供一个框架，不仅可以理解改变的Cuded1核细胞型穿梭及其对Wilms肿瘤发病机理的贡献，而且还需要进行未来独立研究的必要训练。

项目成果

Loss of heterozygosity of succinate dehydrogenase B mutation by direct sequencing in synchronous paragangliomas.

通过直接测序同步副神经节瘤中琥珀酸脱氢酶 B 突变的杂合性丢失。

• DOI: 10.1016/j.cancergencyto.2009.04.009
• 发表时间: 2009
• 期刊: Cancer genetics and cytogenetics
• 作者: Prasad,Pinki;Kant,JeffreyA;Wills,Marcia;O'Leary,Mandy;Lovvorn3rd,Harold;Yang,Elizabeth
• 通讯作者: Yang,Elizabeth