Determining the molecular organization of TDP-43 in liquid spherical annuli and establishing a designer gene therapeutic strategy to degrade TDP-43 aggregates

在这个新的独立奖（K99/R 00）申请中，候选人提出确定相分离的TAR DNA结合蛋白43（TDP-43）的结构和组成，作为了解TDP-43聚集体背后的病理学的一种手段，并研究改善这些聚集体的方法。候选人将通过合作和课程的结合获得Cryo-EM方法，蛋白质纯化，单分子成像和RNA测序的培训。候选人Yu博士被认为是一位非常有前途的初级研究者，具有良好的生产力（包括自提交本提案以来三篇出版物的中间作者），出色的既往培训和出色的推荐信。 评论者一致认为导师克利夫兰博士非常出色，并评论说他在指导许多成功过渡到独立职业的学员方面有着出色的记录。导师还明确表示，候选人可以带着这项研究建立自己的研究计划。合作者提供了强有力的支持信和额外的培训机会。环境被认为是极好的，有许多职业和科学机会，并明确表明对候选人的机构支持。评审员认为培训计划结构良好，适合候选人的研究和职业目标，并通过包含详细而明确的时间轴而得到进一步加强。拟议的研究被认为是令人兴奋和高度创新的，有可能对该领域产生重大影响。该研究计划包括使用最先进的方法和技术，并将为候选人提供一个坚实的基础，使其能够开始独立的职业生涯。评论者指出了研究计划的一些小限制，包括不清楚实验中将使用什么样的样本。研究计划也被认为有点冒险，可能过于雄心勃勃，但审查人员指出，考虑到候选人表现出的生产力，这是一个微不足道的问题。总之，专家组认为这是一个令人兴奋的提案，来自一个优秀的候选人，只有微不足道的小缺点，稍微降低了一些评审员的热情。 正如最后得分所反映的那样，大多数评审员认为这是一个优秀的提案，而其他人则将其评为优秀或非常好。

In this new Pathway to Independence Award (K99/R00) application the candidate proposes to determine the structure and composition of phase separated TAR DNA-binding protein 43 (TDP-43) as a means to understand the pathology behind TDP-43 aggregates and to investigate approaches to ameliorate these aggregates. The candidate will acquire training in Cryo-EM methods, protein purification, single molecule imaging, and RNA sequencing through a combination of collaborations and coursework. The candidate, Dr. Yu, was regarded as an extremely promising junior investigator, with good productivity (including middle authorship on three publications since submission of this proposal), excellent previous training, and outstanding letters of recommendation. Reviewers agreed that the mentor, Dr. Cleveland, was excellent and remarked that he has an outstanding track record of mentoring many trainees who successfully transitioned to independent careers. The mentor also clearly stated that the candidate can take this research with him to establish his own research program. Collaborators provided strong letters of support and additional training opportunities. The environment was regarded as excellent, with many career and scientific opportunities available and a clear demonstration of institutional support for the candidate. Reviewers considered the training plan to be well-structured, appropriate to the candidate’s research and career goals, and further strengthened by inclusion of a detailed and clear timeline. The proposed research was regarded as exciting and highly innovative, with the potential to substantially impact the field. The research plan includes the use of state-of-the art methods and technologies and will provide a solid foundation from which the candidate can launch an independent career. Reviewers noted a few minor limitations with the research plan, including that it was not clear what samples would be used in the experiments. The research plan was also regarded as somewhat risky and potentially overly ambitious, but reviewers noted this was a negligible to minor concern given the demonstrated productivity of the candidate. In summary, the panel considered this an exciting proposal from an excellent candidate with only negligible to minor weaknesses that slightly lowered enthusiasm for some reviewers. As reflected in the final scores, most reviewers considered this an excellent proposal while others rated it as either outstanding or very good.