Friday, May 16, 2025
5/16/2025
The role of lysosomal dysfunction in STING-mediated neurodegeneration from trichloroethylene exposure - Project Summary This NIH F31 application is a request for support for Neda Ilieva, the Principal Investigator, to conduct research and career development activities that will equip her with the necessary skills to become an independent researcher. The project aims to investigate the key proteins, pathways, and mechanisms involved in environmentally-caused neurodegenerative diseases, particularly Parkinson’s disease (PD). The primary objective of this research proposal is to explore the role of lysosomal dysfunction and neuroinflammation in dopaminergic degeneration caused by exposure to trichloroethylene (TCE) in the context of PD. Previous work from the lab of Dr. Briana De Miranda, the PI’s sponsor, has shown that experimental exposure to TCE induces nigrostriatal dopaminergic neurodegeneration, motor deficits, endolysosomal dysfunction, neuroinflammation, and alpha-synuclein accumulation. In a feasibility study, we demonstrated that acute TCE inhalation induces lysosomal acidification deficits in a transgenic “Lysosensor” mouse. Furthermore, we showed that TCE exposure results in autophagy lysosomal pathway (ALP) deficits in vitro. We also found that the innate immune response protein, STING, is elevated in the midbrain tissue of animals exposed to TCE via inhalation. However, it is currently unknown whether these lysosomal deficits and neuroinflammation are in tandem with observed pathology or causal in nigrostriatal dopaminergic degeneration. This project aims to increase our understanding of the mechanisms by which lysosomal deficits induced by TCE contribute to neurodegeneration and neuroinflammation (Aim 1) and whether STING neuroinflammation is the driving factor for dopaminergic degeneration (Aim 2). The long-term objective of the PI’s research is to identify the role of environmental exposures in altering molecular pathways related to normal cellular function and to identify disease-modifying therapeutic strategies to stop the progression of the disease. The proposed training plan for Neda Ilieva is sponsored by Dr. Briana De Miranda and co-sponsored by Dr. David Standaert. The main objective of this plan is to equip Neda with the necessary conceptual and technical skills required to establish a strong foundation for a career in academic research. The plan has been developed with activities that focus on three crucial areas: 1) Conceptual and technical research, including studies in neurodegeneration, cognition, and neurotoxicology; 2) Statistical rigor, reproducibility, and transparency, including training in ethical research practices; and 3) Career development, including mentorship, teaching, and scientific communication. This proposal aims to uniquely prepare Neda to conduct rigorous hypothesis-driven research in neurotoxicology and neurodegenerative disease, while also developing the skills necessary to become a competent scientist, teacher, and mentor in academic science.
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