Therapeutic Target Discovery in a New Mouse Model of Sporadic Amyotrophic Laterl Sclerosis

Myrna working at lab bench

Students

College

Faculty

Researcher in Molecular Biology, Cell Biology, Immunology, and Neuroscience.

Project Summary

As populations age worldwide and life expectancies continue to rise the prevalence of neurodegenerative diseases will increase and collectively become an even larger stressor on the medical and public health care system than they are today (Cire, 2016). This is why it is so critical to find therapeutic strategies to address these disorders. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative diseases in the United States, both of which are devastating to patients and their loved ones. Neither FTD nor ALS have cures or even significant disease-altering therapies, despite several decades of high quality research (Checkoway et al. 2011), possibly because the underlying disease mechanism remains unknown. One potential clue about the disease etiology in both ALS and FTD is that both diseases feature pathological accumulations of TDP-43 protein in affected central nervous system (CNS) areas in patients at the time of death. Because of the potential role TDP-43 may play in these diseases, a transgenic mouse that utilizes mutated human TDP-43 (hTDP-43) to produce pathological and physiological symptoms is useful to model the disease. A transcriptome-wide analysis of this model using RNA Sequencing can probe genetic differences that could elucidate the mechanism of pathological TDP-43-triggered disease. This project takes a biological approach to choosing and analyzing targets from an RNA-Seq dataset in search of a potential therapeutic target for TDP-43 proteinopathies. The systematic validation process sets the groundwork for efficiently sifting through thousands of potential targets, in order to narrow the field of promising genes, which can later be used for drug discovery and treatment of these diseases. We conclude with results from a preclinical prevention study, investigating one example putative target, Abca1.

Overall, this research experience, as part of CURF and in the larger Penn research community, has provided me with invaluable tools. I have learned how to ask appropriate questions in the field and go about studying what is still unknown and how to differentiate failures from setbacks and proceed with new insight and determination. This research opportunity proved to be excellent preparation for medical school and other future endeavors. This includes critical thinking and analysis, presentation and public speaking skills, and several laboratory techniques and research strategies to investigate disease mechanisms, and further, possible therapies to contribute to the scientific field and community larger than our own.