The role for cell cycle regulators in trichloroethylene induced Parkinson's dementia - Project Summary The purpose of this NIH F31 application is to obtain support for the PI, Ashley Adamson, to carry out mentored research and career development activities such that the PI obtains the necessary experience and training to become a rigorous independent researcher. The project goal is to leverage the PI’s current skillset with a rigorous training program to position her to study the key proteins, pathways, and mechanisms behind environmentally caused neurodegenerative diseases, namely Parkinson’s disease dementia. The primary objective of this research proposal is to investigate the role of cell cycle regulatory proteins in facilitating cognitive impairments caused by trichloroethylene exposure in the context of Parkinson’s disease dementia. Work from the lab of Dr. Briana De Miranda, the PI’s sponsor, has shown that exposure to trichloroethylene inhalation induces nigrostriatal dopaminergic neurodegeneration, motor deficits, and alpha-synuclein accumulation in mice. Furthermore, the PI showed that trichloroethylene exposure induces cognitive deficits congruent with those commonly observed in Parkinson’s disease. However, it is currently unknown by what mechanisms trichloroethylene facilitates these deficits. This project aims to increase our understanding of the mechanisms by which cognitive impairment is induced by trichloroethylene exposure by evaluating the roles of aberrant CDK5 activation in pathogenic protein accumulation (Aim 1) and increased cellular senescence in neural stem cell populations (Aim 2). The long-term objective of the PI’s research is to identify the role for environmental exposures in influencing the significant heterogeneity of cognitive symptomology in Parkinson’s disease, and to identify disease modifying therapeutic strategies to stop the progression of the disease. The proposed training plan for Ashley Adamson is sponsored by Dr. Briana De Miranda and co-sponsored by Dr. Erik Roberson. The overall goal of the training plan is to provide Ashley with the conceptual and technical skills necessary to establish a strong foundation for a career in academic research. The training plan has been developed with activities to foster Ashley’s training in 3 crucial areas: 1) conceptual and technical research, including studies in neurodegeneration, cognition, and neurotoxicology; 2) statistical rigor, reproducibility, and transparency; including preparation in ethical research practices; and 3) career development, including training in mentorship, teaching, and scientific communication. This proposal will uniquely prepare the PI to conduct rigorous hypothesis-driven research in neurotoxicology and neurodegenerative disease while also curating the skills necessary for a becoming a competent scientist, teacher, and mentor in academic science.
