Translating Pathomechanisms into Treatment for Spinal Muscular Atrophies

项目总结 脊髓性肌萎缩症(SMA)是导致肌肉衰弱的单基因运动神经元(MN)疾病 身体虚弱，常常过早死亡。我们的研究计划专注于促进两种形式的 SMA：由存活运动神经元1基因(SMN1)的隐性、功能丧失突变引起的近侧型SMA 和由瞬时受体电位香草素4基因显性突变引起的远端SMA(DSMA) (TRPV4)。这项由NINDS Landis导师奖资助的R35拨款的行政补充将 提供资金，加强对约翰·霍普金斯大学四名研究生的指导和培训 医学院以培养他们未来在生物医学领域的职业生涯为长期目标，努力前进 神经退行性疾病的治疗。每个学生都要完成一个毕业论文项目，这个项目在 母公司R35拨款中提议的研究范围：斯蒂芬·布朗和曼迪·登特将专注于近端 SMA和Anna Bagnell和Jonathan Alevy将专注于SMA的远端。他们将利用独特的资源和 最先进的技术来定义限制当前SMA疗法疗效的因素，表征细胞 以及驱动SMA病理的分子机制，并识别和验证新的治疗策略。在……里面 为了促进他们的培训，该副刊的第一个目的是定期为科学工作者提供一对一的会议 讨论包括相关文献回顾、假设生成、实验设计和数据 释义。第二个目标是通过使他们能够利用尖端的实验来促进他们的培训 技术来追求他们的科学假设。第三个目标是支持学生到科学 会议用于演示和网络，第四个目标是为“同行”创建一个丰富的受训人员社区 辅导。

PROJECT SUMMARY Spinal muscular atrophies (SMAs) are monogenetic motor neuron (MN) diseases that cause debilitating muscle weakness and often early mortality. Our research program focuses on advancing therapeutics for two forms of SMA: proximal SMA caused by recessive, loss-of-function mutations of the survival motor neuron 1 gene (SMN1) and distal SMA (dSMA) caused by dominant mutations of the transient receptor potential vanilloid 4 gene (TRPV4). This administrative supplement to my R35 grant funded by the NINDS Landis Mentorship Award will provide funds to augment the mentorship and training of four graduate students at Johns Hopkins University School of Medicine with the long-term goal of fostering their future careers in biomedicine working to advance treatment for neurodegenerative diseases. Each student will pursue a graduate thesis project that is within the scope of research proposed in the parent R35 grant: Stephen Brown and Maddie Dent will focus on proximal SMA and Anna Bagnell and Jonathan Alevy will focus on distal SMA. They will leverage unique resources and state-of-the-art technologies to define factors limiting efficacy of current SMA therapeutics, characterize cellular and molecular mechanisms driving SMA pathology, and identify and validate novel therapeutic strategies. In order to foster their training, the first aim of the supplement is to provide regular one-on-one meetings for scientific discussion including review of relevant literature, hypothesis generation, experimental design, and data interpretation. The second aim to foster their training by enabling them to utilize cutting-edge experimental techniques to pursue their scientific hypotheses. The third aim is to support travel of students to scientific meetings for presentations and networking and the fourth aim is to create a rich community of trainees for “peer” mentoring.