Translating Pathomechanisms into Treatment for Spinal Muscular Atrophies

项目摘要 脊髓性肌萎缩症（SMA）是单基因运动神经元（MN）疾病，导致肌肉衰弱 虚弱且通常过早死亡。我们的研究计划侧重于推进两种形式的 SMA：由运动神经元生存基因1（SMN1）的隐性功能丧失突变引起的近端SMA 和由瞬时受体电位香草酸4基因显性突变引起的远端SMA（dSMA） （TRPV4）。这是对我的R35补助金的行政补充，由NINDS Landis导师奖资助， 为约翰霍普金斯大学的四名研究生提供指导和培训 医学院的长期目标是培养他们未来在生物医学方面的职业生涯， 神经退行性疾病的治疗。每个学生将追求一个研究生论文项目，是在 在父母R35补助金中提出的研究范围：Stephen Brown和Maddie Dent将专注于近端 SMA和安娜巴格内尔和乔纳森阿列维将重点关注远端SMA。他们将利用独特的资源， 最先进的技术，以确定限制当前SMA治疗有效性的因素，表征细胞 以及驱动SMA病理的分子机制，并确定和验证新的治疗策略。在 为了促进他们的培训，补编的第一个目标是为科学家提供定期的一对一会议， 讨论包括相关文献综述、假设生成、实验设计和数据 解释。第二个目标是通过使他们能够利用尖端的实验技术来促进他们的培训。 技术来追求他们的科学假设。第三个目标是支持学生前往科学 第四个目标是为“同行”建立一个丰富的受训者社区， 指导。

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.