BLR&D Research Career Scientist Award Application

这项研究职业科学家（RCS）奖的续期申请旨在继续进行中的研究 现任者的活动集中在主要尿路疾病的分子发病机制上 包括膀胱癌和肾结石在内的疾病。这两种疾病在退伍军人中都很普遍， 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非常有限， 从而阻碍了新的诊断、治疗和预防战略的发展。在过去 在授予期间，RCS实验室在确定关键遗传和 表观遗传决定因素是膀胱癌和肾结石发生和发展的基础。与 关于膀胱癌，RCS的实验室确定了几个特定的组合遗传驱动因素 它们负责膀胱癌的两种主要表型变体的发生和发展， 例如，在一个实施例中，低度浅表乳头状肿瘤与高度浸润性肿瘤。使用广泛的 包括培养的细胞系，基因工程小鼠，化学致癌作用， 通过对人体标本的分析和高通量分析，实验室发现， 酪氨酸激酶（RTK）/RAS/PI 3 K途径与9 p21肿瘤抑制因子的丧失协同作用（例如，CDKN2A 和CDKN 2B）诱导低级别浅表性乳头状膀胱癌， RTK/RAS/PI 3 K通路与RB家族蛋白或p53通路的缺陷协同作用 诱发高级别肌肉浸润性膀胱癌的效应物。在另一系列由VA支持的研究中， 优异评论奖，RCS的实验室证明，丙酮酸激酶2（PKM 2），一种关键酶， 无氧糖酵解或瓦尔堡效应在大多数膀胱癌中上调，并在膀胱癌中起关键作用。 膀胱癌细胞增殖，PKM 2的基因切除显著降低膀胱癌细胞的生长， 体外和体内。通过RNAi或小分子抑制PKM 2也大大降低了获得性抗性。 顺铂的膀胱癌细胞。这些数据和提案中要详细说明的其他数据在以下方面非常重要： 不仅提高了我们对膀胱癌发病机制的分子基础的理解， 膀胱癌诊断和治疗的新策略的实用见解。关于肾脏 斯通，RCS的实验室继续在揭示作用和机制方面取得重大进展， Tamm-Horsfall蛋白（THP或尿调节素）是人类最丰富的尿蛋白，在尿中的作用 防止肾结石形成。THP的缺乏使动物模型更易受影响 肾内钙化，通过增加尿液过饱和度，这非常类似于早期阶段的 人类特发性结石形成。由于THP缺乏症经常在患者中观察到，因此这些数据将 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（PO 1）补助金和NIH RO 1补助金; 发表了49篇同行评审论文;率先与VA和非VA开展了多个合作项目 研究人员;继续积极培训初级教员和博士后研究员;提供重要的 为当地和国家退伍军人事务部、大学附属机构和整个研究界提供服务。这些 这些成就为RCS继续和扩大他对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，病人护理，指导，服务和 跨学科合作。

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.