BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10703154
• 负责人: Haining Zhu
• 金额: --
• 依托单位: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703154
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Arizona; Award; Binding; Boston; Brain; Cells; Chromatin; Collaborations; Communication; Communities; Complex; Contracts; Cytoplasm; Cytoplasmic Granules; Defect; Disease; Drosophila genus; Equilibrium; Frontotemporal Dementia; Functional disorder; Funding; Future; Genes; Genetic Models; Genets; Goals; Health Benefit; Healthcare; Healthcare Systems; Joints; Journals; Karyopherins; Laboratories; Laboratory Finding; Liquid substance; Mediating; Mission; Modeling; Molecular; Motor Neurons; Mutation; Nature; Neurodegenerative Disorders; Neuronal Dysfunction; Neurosciences; Nonsense-Mediated Decay; Nuclear; Nuclear Fusion; Pathogenesis; Pathologic; Patients; Phase; Physiological; Play; Productivity; Property; Protein Biosynthesis; Proteins; Published Comment; Publishing; RNA; RNA Decay; RNA metabolism; RNA-Binding Proteins; Research; Research Support; Resources; Retirement; Role; Scientist; Services; Site; Specificity; Structure; System; Testing; Toxic effect; Transcriptional Regulation; Translational Research; Translations; Veterans; Work; aging population; biobank; career; cohort; drug development; effective therapy; empowerment; familial amyotrophic lateral sclerosis; fused in sarcoma; gain of function; high risk; induced pluripotent stem cell; innovation; insight; loss of function; mRNA Decay; military veteran; mutant; mutation carrier; neuron loss; new therapeutic target; novel; nucleocytoplasmic transport; operation; programs; receptor; research and development; resilience factor; sporadic amyotrophic lateral sclerosis; success; therapeutic development; translational impact

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.

肌萎缩侧索硬化症 (ALS) 是一种人们知之甚少的神经退行性疾病，其特征是 迄今为止，ALS 主要是由于运动神经元死亡而没有有效的治疗方法，已被指定为一项服务。 由于退伍军人感染这种毁灭性致命疾病的风险更高，因此退伍军人管理局将其与疾病联系起来。 该研究职业科学家 (RCS) 申请的 PI 朱海宁博士已在 ALS 领域工作 20 年 自他开始独立学术生涯以来，他的研究计划的长期目标是 更好地确定 ALS 疾病发病机制和进展的分子机制。 除了机械理解之外，他的实验室还从事转化研究以发现新颖的 治疗目标并确定用于药物开发的化合物将有助于他的研究计划的成功。 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 资助的优异项目是研究肉瘤中融合的 RNA 结合蛋白 (FUS)，该蛋白 与家族性和散发性 ALS 相关，家族性 ALS 约占所有 ALS 的 10-15%。 病例和 ALS 基因为研究可能的机制提供了急需的“分子手柄” 与所有 ALS 病例相关，他的实验室一直致力于研究 FUS 蛋白在生理条件下的功能。 他的实验室取得了一些新的发现，包括鉴定了 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 形成复合物（Niu，2012），以及其中之一的表征 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 染色质结合和转录调控（Yang，2014）他的实验室也发现FUS阳性。 颗粒中含有参与蛋白质翻译和 RNA 无义介导的衰变 (NMD) 的蛋白质。 此外，突变体 FUS 抑制蛋白质翻译和过度激活 NMD（Kamelgarn，2018）。 被认为非常重要，以至于《美国国家科学院院刊》发表了附带的评论。 在当前资助期间（2020 年续签至 2024 年），总体假设是 蛋白质翻译失调和 RNA 无义介导的衰变 (NMD) 会导致 FUS 毒性和 他的实验室建议确定 (1) 突变型 FUS 的哪些特性驱动了运动神经元功能障碍。 蛋白质翻译和 NMD 失调；(2) mRNA 衰减和蛋白质翻译是否受到影响； 具有任何特异性的突变FUS；以及（3）这些缺陷的纠正是否恢复了之间的平衡 蛋白质翻译和 NMD。 在拟议的 RCS 期间，朱博士计划通过重点关注三个方面来扩展他的研究计划 第一个方向是利用家族性 ALS 队列中独特的未受影响的突变携带者来识别。 第二个因素是使用源自患者的 iPSC 细胞系进行转化研究和治疗。 第三是识别和优化更好的化合物，以促进 PTC 通读。 相关神经退行性疾病——额颞叶痴呆（FTD）的潜在疗法。 朱博士于 2021 年 7 月搬迁至亚利桑那州图森市后，积极从事多项职能和工作 朱博士开始担任南亚利桑那州退伍军人医疗系统 (SAVAHCS) 的现场 PI。 VA 生物储存库脑库 (BBB)，这是整个 VA 系统中唯一的 ALS 生物储存库。 与波士顿 VA 的合作为整个 ALS 研究界提供了重要资源。 他领导了一项富有成效的研究项目，并在地方和国家层面的 VA 委员会任职。 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 研究方面不断取得进展，造福退伍军人的医疗保健。