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BLR&D Research Career Scientist Award Application

BLR

基本信息

批准号：
10293576
负责人：
XUE-RU WU
金额：
--
依托单位：
VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10293576
关键词：
9p21 Ablation Affect Age-Years American American Cancer Society Animal Model Appointment Award Basic Science Biochemistry Biological Biological Markers Bladder Bladder Neoplasm CDKN2A gene Cancer Diagnostics Cancer Etiology Cell Line Cell Proliferation Cellular biology Cisplatin Clinical Clinical Management Clinical Research Communities Data Dependence Development Diagnosis Disease Disease Management Doctor of Philosophy Economic Burden Education Emotional Enzymes Epigenetic Process European Event Expenditure Faculty Female Foundations Funding General Population Genes Genetic Genetically Engineered Mouse Goals Grant Growth Growth Factor Receptors Healthcare Healthcare Systems Human In Vitro Incidence Journals Kidney Kidney Calculi Knock-in Knock-out Knowledge Laboratories Laboratory Research Lesion Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Medical Mentors Minor Mission Modality Modeling Molecular Morbidity - disease rate Mus Names Nature New York Oncogenes Pain Paper Papillary Papillary Neoplasm Pathogenesis Pathway interactions Patient Care Patients Peer Review Persons Phenotype Physical Sufferings Play Postdoctoral Fellow Prevalence Prevention Prevention strategy Principal Investigator Procedures Process Prognosis Program Research Project Grants Protein Family Proteins Publishing Pyruvate Kinase Quality of life RNA Interference Receptor Activation Receptor Protein-Tyrosine Kinases Recurrence Research Research Activity Research Personnel Research Support Resistance Risk Role Scientist Series Services Signal Pathway Smoker Smoking Specimen Spinal cord injury Surveys TP53 gene Therapeutic Time Tobacco smoking behavior Training Transgenic Organisms Translational Research Tumor Suppressor Genes Tumor Suppressor Proteins Tumorigenicity UMOD gene United States National Academy of Sciences United States National Institutes of Health Universities Urinary tract Urologic Diseases Urology Ursidae Family Variant Veterans Warburg Effect Woman aging population anaerobic glycolysis anticancer research base body system calcification cancer cell cancer initiation cancer therapy carcinogenesis career chemical carcinogenesis clinical investigation combinatorial cost disorder prevention dosage improved in vivo insight interdisciplinary collaboration interest lifetime risk lost work time male member men molecular subtypes mortality mouse model multidisciplinary muscle invasive bladder cancer neglect non-smoker novel novel diagnostics novel strategies overexpression pain relief small molecule smoking-related cancer socioeconomics targeted treatment tool treatment strategy tumor tumor initiation tumor progression urinary urologic

项目摘要

This renewal application for Research Career Scientist (RCS) award seeks to continue the ongoing research activities by the incumbent that have been focused on the molecular pathogenesis of major urinary tract diseases including bladder cancer and kidney stone. Both diseases are highly prevalent among the Veterans, and inflict considerable emotional and physical suffering and staggering medical expenses. Despite the socioeconomic impact, research into the molecular pathogenesis of these diseases remains extremely limited, thus hampering the development of new diagnostic, therapeutic and preventive strategies. During the last award period, the laboratory of the RCS has made significant inroads in defining the key genetic and epigenetic determinants underlying the initiation and progression of bladder cancer and kidney stone. With respect to bladder cancer, the laboratory of the RCS identified several specific combinatorial genetic drivers that are responsible for the genesis and progression of the two major phenotypic variants of bladder cancer, e.g., low-grade superficial papillary tumors versus high-grade invasive tumors. Using a broad range of technical approaches including cultured cell lines, genetically engineered mice, chemical carcinogenesis, analysis of human specimens and high-throughput profiling, the laboratory found that the activation of receptor tyrosine kinase (RTK)/RAS/PI3K pathway collaborates with the loss of 9p21 tumor suppressors (e.g., CDKN2A and CDKN2B) to induce low-grade superficial papillary bladder cancer, and that the same activated RTK/RAS/PI3K pathway collaborates with the deficiency of RB family proteins or that of the p53 pathway effectors to induce high-grade muscle-invasive bladder cancer. In another series of studies supported by a VA Merit Review award, the laboratory of the RCS demonstrated that pyruvate kinase 2 (PKM2), a key enzyme in anaerobic glycolysis or Warburg effect, is upregulated in most bladder cancers and plays a critical role in bladder cancer cell proliferation, and that genetic ablation of PKM2 markedly reduces bladder cancer growth in vitro and in vivo. Inhibition of PKM2 by RNAi or small molecules also greatly decreases the acquired resistance of bladder cancer cells to cisplatin. These and other data to be detailed in the proposal are highly significant in not only improving our understanding of the molecular bases of bladder cancer pathogenesis, but also offer practical insights into novel strategies for bladder cancer diagnostics and treatment. With respect to kidney stone, the laboratory of the RCS continued to make major progress in unraveling the role and mechanisms of action of Tamm-Horsfall protein (THP or uromodulin), the most abundant urinary protein in humans, in urinary tract defense against kidney stone formation. The deficiency of THP renders animal models more susceptible to intra-renal calcification, via increased urinary supersaturation, that strongly resembles the early stages of idiopathic stone formation in humans. Because THP deficiency is often observed in patients, such data will have major implications on kidney stone pathogenesis and prevention. In the past four and a half years, the RCS obtained a VA Merit Award, a multidisciplinary NIH Program Project (PO1) grant and an NIH RO1 grant; published 49 peer-reviewed papers; spearheaded multiple collaborative projects with VA and non-VA investigators; continued to actively train junior faculty members and postdoctoral fellows; provided important services to local and national VA, university affiliates and research community at large. These accomplishments set the stage for the RCS to continue and expand his contributions to the mission of VA and university affiliates in helping advance research, education, patient care, mentoring, services and interdisciplinary collaborations.

此次研究职业科学家（RCS）奖的续签申请旨在继续正在进行的研究现任者的活动重点是主要泌尿道的分子发病机制疾病包括膀胱癌和肾结石。这两种疾病在退伍军人中非常流行，并造成相当大的精神和身体痛苦以及惊人的医疗费用。尽管社会经济影响，对这些疾病的分子发病机制的研究仍然极其有限，从而阻碍了新的诊断、治疗和预防策略的开发。最后期间颁奖期间，RCS 实验室在定义关键遗传和膀胱癌和肾结石的发生和进展的表观遗传决定因素。和关于膀胱癌，RCS 实验室确定了几种特定的组合遗传驱动因素负责膀胱癌两种主要表型变异的发生和进展，例如，低级别浅表乳头状肿瘤与高级别浸润性肿瘤。使用广泛的技术方法包括培养细胞系、基因工程小鼠、化学致癌、通过对人体标本的分析和高通量分析，实验室发现受体的激活酪氨酸激酶 (RTK)/RAS/PI3K 通路与 9p21 肿瘤抑制因子（例如 CDKN2A 和 CDKN2B）诱导低度浅表性乳头状膀胱癌，并且同样激活 RTK/RAS/PI3K 通路与 RB 家族蛋白或 p53 通路缺陷相关诱导高级别肌肉浸润性膀胱癌的效应器。在 VA 支持的另一系列研究中优异评审奖，RCS 实验室证明丙酮酸激酶 2 (PKM2)，一种关键酶无氧糖酵解或 Warburg 效应在大多数膀胱癌中表达上调，并在膀胱癌细胞增殖，并且 PKM2 的基因消除显着降低了膀胱癌细胞的生长体外和体内。 RNAi或小分子对PKM2的抑制也大大降低了获得性耐药性膀胱癌细胞对顺铂的影响。提案中详细说明的这些数据和其他数据对于以下方面非常重要：不仅提高了我们对膀胱癌发病机制的分子基础的理解，而且还提供了对膀胱癌诊断和治疗新策略的实际见解。就肾脏而言 Stone表示，RCS实验室在阐明其作用和机制方面继续取得重大进展 Tamm-Horsfall 蛋白（THP 或尿调节蛋白）是人类最丰富的尿蛋白，在尿中的作用防止肾结石形成的道防御。 THP 的缺乏使动物模型更容易受到影响通过增加尿液过饱和度导致肾内钙化，这与早期阶段非常相似人类特发性结石形成。由于患者中经常观察到 THP 缺乏症，因此此类数据将对肾结石的发病机制和预防具有重要意义。在过去的四年半里， RCS 获得了 VA 优异奖、多学科 NIH 计划项目 (PO1) 拨款和 NIH RO1 拨款；发表49篇同行评审论文；与 VA 和非 VA 牵头开展多个合作项目调查员；继续积极培养初级教师和博士后；提供重要的为当地和国家退伍军人管理局、大学附属机构和整个研究界提供服务。这些所取得的成就为 RCS 继续并扩大他对 VA 使命的贡献奠定了基础，大学附属机构帮助推进研究、教育、患者护理、指导、服务和跨学科合作。