BLRD Research Career Scientist Award Application

申请者的整体研究计划寻求发展新的见解和对关键的理解 调节免疫细胞功能和免疫细胞之间相互作用的分子机制，与特定的 重点是B和T淋巴细胞，以及B细胞来源的肿瘤。最终目标是将这一知识应用于 制定改进措施，以预防和治疗涉及淋巴细胞的疾病，以及 告知临床选择特定退伍军人肿瘤的最佳可用治疗方法。最基本的 30年前在申请人的实验室开始的科学调查现在导致了重要的 与内科科学家合作，将这些研究的结果转化为治疗和临床 审判。在这项SRCS奖励的拟议资助期内将开展的项目及其相关性 为了老兵的健康，包括以下内容。 1)确定信号蛋白肿瘤坏死因子受体相关蛋白3(TRAF3)作为肿瘤抑制因子的作用 在B细胞癌中。B细胞淋巴瘤和多发性骨髓瘤是最常见的癌症 在退伍军人中，淋巴细胞在人类中的比例过高。在BCL和MM中，功能丧失 TRAF3突变是常见的，申请人发现翻译后TRAF3蛋白的丢失可以 也会发生。拟议的项目将继续定义TRAF3如何抑制哪些生存途径，何时 调控失调，参与bcl/MM发病机制，确定TRAF3如何调节bcl代谢，确定 衰老B细胞中TRAF3蛋白翻译后丢失的机制及生物学后果 并为多发性骨髓瘤启动细胞开发新的生物标志物。重要的是，所有这些项目都将涉及正在进行的 与临床医生同事的合作。2)确定TRAF3在其他免疫细胞中的临床相关作用 类型。申请人的实验室将继续研究TRAF3如何增强和调节T细胞的功能 淋巴细胞，对人类对传染病和肿瘤的免疫反应至关重要。一个新项目，在 与两名内科科学家合作，调查了单等位基因TRAF3中断在 导致人类对感染和自身免疫的慢性易感性。我们强烈怀疑这种基因 事实上，缺陷比之前意识到的要普遍得多。3)翻译申请人的知识 CD40功能进入临床应用这涉及到一些项目，这些项目试图优化一个敌对的反人类 CD40抗体用于阻断移植排斥反应，这是一个与退伍军人相关的临床问题，并 了解CD40在抵抗埃博拉病毒感染中所起的保护作用。4)提供关键专业知识 在B淋巴细胞生物学领域资助多发性骨髓瘤和胰腺癌的合作项目。这两种恶性肿瘤 在退伍军人中的发病率高于正常水平。除了这四个主要项目领域外， 从主要的研究目标来看，申请者将继续她在指导方面的坚定承诺和活动 教授下一代生物医学研究人员，包括博士和医学博士，并服务于科学 社区在委员会的参与、赠款和手稿的审查以及在科学研究中的领导作用 社会。

The overall research program of the applicant seeks to develop new insights and understanding of the key molecular mechanisms regulating the functions of, and interactions between immune cells, with a particular emphasis on B and T lymphocytes, and B cell-derived tumors. The ultimate goal is to apply this knowledge to development of improved measures to both prevent and treat diseases involving lymphocytes, as well as to inform the clinical selection of the optimal available treatments for a specific Veteran's tumor. The basic science investigations that began in the applicant's laboratory 30 years ago are now leading to important collaborations with physician-scientists to translate the findings of these studies into treatments and clinical trials. The projects to be pursued during the proposed funding period of this SRCS award, and their relevance to Veteran health, include the following. 1) Define the role of the signaling protein TNF Receptor Associated Protein 3 (TRAF3) as a tumor suppressor in B cell cancers. B cell lymphoma (BCL) and multiple myeloma (MM), the most common cancers of lymphocytes in humans, are over-represented in the Veteran population. In both BCL and MM, loss-of-function TRAF3 mutations are common, and the applicant discovered that post-translational loss of TRAF3 protein can also occur. The proposed project will continue to define how TRAF3 restrains survival pathways which, when dysregulated, contribute to BCL/MM pathogenesis, define how TRAF3 regulates BCL metabolism, determine the mechanisms and biological consequences of post-translational loss of TRAF3 protein in the B cells of aging humans, and develop new biomarkers for MM-initiating cells. Importantly, all these projects will involve ongoing collaborations with clinician colleagues. 2) Determine clinically-relevant roles of TRAF3 in other immune cell types. The applicant's lab will continue studies revealing how TRAF3 enhances and regulates the function of T lymphocytes, critical to human immune responses to infectious disease and tumors. A new project, in collaboration with two physician-scientists, investigates the consequences of monoallelic TRAF3 disruption in humans, leading to chronic susceptibility to infections, and autoimmunity. We strongly suspect that this genetic defect is in fact much more widespread than previously appreciated. 3) Translate the applicant's knowledge of CD40 function into clinical application. This involves projects that seek to optimize an antagonistic anti-human CD40 antibody for use in blocking transplant rejection, a clinical problem of relevance to Veterans, and to understand the protective role played by CD40 in resistance to Ebola virus infection. 4) Provide key expertise in B lymphocyte biology to funded collaborative projects in MM and pancreatic cancer. Both these malignancies occur at higher-than-normal rates in the Veteran population. In addition to these 4 major project areas, which form the major research Aims, the applicant will continue her strong commitment and activities in mentoring and teaching the next generation of biomedical researchers, both PhD and MD, and serve the scientific community in committee participation, review of grants and manuscripts, and leadership roles in scientific societies.