The goal of this application is to establish a focused training plan to successfully advance my research and career goals during the award period. The details provided in this proposal include specific action steps for me to gain training in career skills that I have had little exposure to that include, for example, effective grantsmanship mentoring, and laboratory management. Furthermore, to realize my research goals, I am in need of training in new scientific fields, those of high-throughput screening assays and chemical biology. To that end, I have recently established a collaboration with the laboratory of Dr. James Inglese, director of the Assay Development and Screening Technologies Laboratory in the National Center for Advancing Translational Sciences (NCATS), who will serve as my co-mentor as described below. These proposed training activities are necessary to prepare me for a successful transition to an independent investigator position. All aspects of my training will be supported by an Advisory Committee comprised of five leading scientists with distinct scientific and career expertise in both intramural and extramural research. The goal of my research program is to develop an innovative research plan aimed at leveraging the chemical diversity of high-throughput screening (HTS) libraries to explore the modulation of RNA structure by exogenous ligands, a novel methodology I refer to as HTS-MoRSEL. By targeting RNA folding directly, rather than binding, small molecule ligands will be identified that control the folding/function of nearly any structured RNA. This high-impact research program has broad implications for probing structure-function relationships within the expanding field of RNA biology. During the award period, I will identify ligands modulating the folding and function of several RNAs of biomedical significance. For example, I will examine RNAs that regulate genes responsible for viral replication or virulence in pathogenic bacteria. Additionally, I will apply tis methodology to identify ligands capable of modulating the structure of a human oncogenic microRNA polycistron; the structure and folding of this large RNA transcript are responsible for autoregulating its processing by the RNAi pathway machinery. Together, my results will present a new paradigm for the design of therapeutics targeting RNA and the development of synthetic biology tools. While I have demonstrated exceptional research success both in my Ph.D. and post-doctoral studies, the new direction of my proposed research plan necessitates additional training that will build on my existing training. Specifically, only having been introduced recentl to HTS chemical biology methodologies, I am working to establish my proficiency employing this approach. Given the prominence of these assays in my proposed research program, I am in need of focused training in this field during the mentored phase of the award period. I recently established a collaboration with Dr. James Inglese, who has agreed to serve as co-mentor during this award. I will receive focused training in his laboratory towards the development of appropriate HTS assays for my RNA folding studies. Under this Career Transition Award I will also receive necessary additional training in the lab of my mentor, Dr. Ferr-D'Amar (RNA Biophysics and Cellular Physiology, NHLBI) for the molecular and atomistic characterization studies of RNA-ligand interactions identified in my HTS studies. The existing state-of-the-art instrumentation resources within these labs are more than sufficient to complete all aspects of this proposed research program. Both Dr. Ferr-D'Amar and Dr. Inglese will work together to provide me with necessary career development training for establishing an independent research lab. Uniquely, following this training I will be aptly qualified to perform both HTS assay and molecular characterization of RNA-ligand interactions. Together, these combined approaches will make me a highly qualified candidate to lead an independent research laboratory. The environment within the NHLBI, NCATS, and NIH are exceptionally suited for the development of all aspects of this award application. Along with the scientific resources, the NIH offers extensive career development programs for post-doctoral researchers (e.g. the Career Advancement Toolkit Track) through the Office of Intramural Education and Training, headed by Dr. Sharon Milgram. Furthermore, Dr. Herbert Geller, director of the NHLBI Office of Education, offers many complementary resources and will provide me with individualized career development guidance. In summary, under the NHLBI Career Transition Award, I will receive specific training in research and career development areas in which I have had little exposure to date including, but not limited to, HTS assay development, mentoring, teaching, and lab management. Subsequent to this training I will be excellently positioned to achieve my career goal of establishing a high-impact, independent research laboratory at an academic university.
This research will develop a novel methodology for controlling the functions of biological RNAs by altering their three---dimensional shapes. This represents a novel paradigm for targeting RNAs with new therapeutics and expands the scope of potential RNA drug targets.
| Yu, Hao; Dranchak, Patricia; Li, Zhiru et al. (2017) Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases. Nat Commun 8:14932 |
| Baird, Nathan J; Inglese, James; Ferré-D'Amaré, Adrian R (2015) Rapid RNA-ligand interaction analysis through high-information content conformational and stability landscapes. Nat Commun 6:8898 |
