BLRD Research Career Scientist Award Application

肌萎缩侧索硬化症（ALS）是一种知之甚少的神经退行性疾病，其特征在于 主要是运动神经元死亡，迄今为止还没有有效的治疗方法。ALS已被指定为服务 由于退伍军人感染这种毁灭性和致命的疾病的风险更高，因此退伍军人管理局正在研究一种与退伍军人相关的疾病。 本研究职业科学家（RCS）应用程序的PI，朱海宁博士，一直致力于ALS 20 多年来，他开始了独立的学术生涯。他的研究计划的长期目标是 确定ALS疾病发病机制和进展的分子机制。由更好授权 机械的理解，他的实验室也从事翻译研究，以发现新的 治疗靶点，并确定用于药物开发的化合物。他的研究计划的成功将 有利于退伍军人的医疗保健，特别是那些患有ALS的人。 朱博士的VA资助的Merit项目是研究融合在肉瘤中的RNA结合蛋白（FUS）， 与家族性和散发性肌萎缩侧索硬化症有关家族性ALS约占所有ALS患者的10-15%。 病例和ALS基因提供了急需的“分子把手”，用于研究可能导致ALS的机制。 与所有ALS病例相关。他的实验室一直在研究FUS蛋白在生理条件下的功能， 和病理条件。他的实验室已经取得了几项新的发现，包括鉴定出 FUS中的核定位序列（NLS）（Gal，2011），FUS NLS晶体结构的测定 与核转运受体转运蛋白1复合（Niu，2012），以及其中一种 第一个果蝇模型（Xia，2012）。他的两项研究分别于2014年和2018年发表在PNAS上。 他的实验室证明，FUS蛋白的液-液相分离（LLPS）发挥了关键作用 在染色质结合和转录调节中的作用（Yang，2014）。他的实验室还发现， 颗粒含有参与蛋白质翻译和RNA的无义介导的衰变（NMD）的蛋白质。 此外，突变型FUS抑制蛋白质翻译和过度激活的NMD（Kamelgarn，2018）。这项工作 被认为是如此重要，PNAS发表了一个附带的评论。 在当前的资助期（2020年延长至2024年），首要假设是， 蛋白质翻译和RNA无义介导的衰变（NMD）的失调导致FUS毒性， 运动神经元功能障碍他的实验室提出要确定（1）突变FUS的哪些特性驱动了 蛋白质翻译和NMD的失调;（2）mRNA降解和蛋白质翻译是否受到影响 通过突变FUS与任何特异性;和（3）是否纠正这些缺陷恢复之间的平衡 蛋白质翻译和NMD。 在建议的RCS期间，朱博士计划通过专注于三个方面来扩大他的研究计划。 方向第一种是使用家族性ALS队列中独特的未受影响的突变携带者来识别 弹性因素。第二个是使用患者来源的iPSC系进行转化研究和治疗。 发展第三是识别和优化更好的化合物，以促进PTC通读， 潜在的治疗相关的神经退行性疾病，额颞叶痴呆症（FTD）。 在2021年7月搬迁到亚利桑那州图森市后，朱博士积极从事多项职能， 南亚利桑那州VA医疗保健系统（SAVAHCS）。朱医生开始担任研究中心PI VA Biorepository Brain Bank（BBB）是整个VA系统中唯一的ALS生物库。这一联合 与波士顿VA的合作为整个ALS研究社区提供了关键资源。除了 领导一个富有成效的研究计划，他在地方和国家层面的退伍军人事务委员会。他 与许多VA和非VA科学家合作。RCS项目的支持将使朱博士能够 在ALS研究方面取得持续进展，并使退伍军人的医疗保健受益。

Amyotrophic lateral sclerosis (ALS) is a poorly understood neurodegenerative disease characterized predominantly by motor neuron death with no effective treatment to date. ALS has been designated as a service connected disease by VA since Veterans are at a higher risk of contracting this devastating and fatal disease. The PI of this Research Career Scientist (RCS) application, Dr. Haining Zhu, has been working on ALS for 20 years since he started his independent academic career. The long-term goal of his research program is to determine the molecular mechanisms of ALS disease pathogenesis and progression. Empowered by better mechanistic understandings, his laboratory is also engaged in translational research to discover novel therapeutic targets and to identify compounds for drug development. The success of his research program will benefit the healthcare of veterans, particularly those afflicted with ALS. Dr. Zhu's VA-funded Merit project is to study the RNA binding protein Fused in Sarcoma (FUS), which has been implicated in both familial and sporadic ALS. Familial ALS represents approximately 10-15% of all cases and ALS genes provide much-needed “molecular handles” for studying mechanisms that might be relevant to all ALS cases. His laboratory has been working on the function of FUS protein under physiological and pathological conditions. His laboratory has made several novel findings, including the identification of the nuclear localization sequence (NLS) in FUS (Gal, 2011), the determination of the crystal structure of FUS NLS in complex with the nuclear transport receptor transportin 1 (Niu, 2012), and the characterization of one of the first Drosophila models (Xia, 2012). Two of his studies were published in PNAS in 2014 and 2018, respectively. His laboratory demonstrated that liquid-liquid phase separation (LLPS) of the FUS protein played a critical role in chromatin binding and transcription regulation (Yang, 2014). His laboratory also found that FUS-positive granules contained proteins involved in protein translation and nonsense-mediated decay (NMD) of RNA. Moreover, mutant FUS suppressed protein translation and hyper-activated NMD (Kamelgarn, 2018). This work was considered so significant that PNAS published an accompanying Commentary. In the current funding period (renewed in 2020 until 2024), the overarching hypothesis is that the dysregulation of protein translation and RNA nonsense-mediated decay (NMD) contributes to FUS toxicity and motor neuron dysfunction. His laboratory proposed to determine (1) what properties of mutant FUS drive the dysregulation of protein translation and NMD; (2) whether mRNA decay and protein translation are impacted by mutant FUS with any specificity; and (3) whether corrections of these defects restore the balance between protein translation and NMD. During the proposed RCS period, Dr. Zhu plans to expand his research program by focusing on three directions. The first is to use the unique unaffected mutation carriers in the familial ALS cohort to identify resilience factors. The second is to use patient-derived iPSC lines for translational research and therapeutic development. The third is to identify and optimize better compounds to promote PTC readthrough as a potential therapy for a related neurodegenerative disease, frontotemporal dementia (FTD). After relocating to Tucson, AZ in July 2021, Dr. Zhu has actively engaged in several functions and collaborations at Southern Arizona VA Healthcare System (SAVAHCS). Dr. Zhu started to serve as the site PI of VA Biorepository Brain Bank (BBB), which is the sole ALS biorepository in the entire VA system. This joint operation with the Boston VA provides a critical resource for the entire ALS research community. In addition to leading a productive research program, he serves on VA committees at the local and national levels. He collaborates with many VA and non-VA scientists. The support from the RCS program will enable Dr. Zhu to make continuous progress in ALS research and to benefit the healthcare of veterans.