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.
Nuclear clearance and cytoplasmic aggregation of TAR DNA binding protein 43 (TDP-43) in motor and cortical neurons is a broad pathological hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and also highly correlates with APOE4-associated Alzheimer?s disease. The proposed research will utilize innovative and multidisciplinary approaches to identify the molecular basis of TDP-43 phase separation into intranuclear spherical annuli, which will elucidate how TDP-43 regulate alternative splicing and how TDP-43 aggregates in the cytoplasm. I also propose to establish a new concept of treating TDP-43 aggregation by selectively degrade the aggregated protein, which can also be applied to degrades other cytoplasmic protein aggregates in different neurodegenerative diseases.
