Interactions Between the Immune System, Genetics, and Environmental Mitochondrial Toxicants in Models of Parkinson s Disease
Abstract
Study Objectives and Rationale Parkinson s disease (PD) is the most common neurodegenerative movement disorder, and it affects over 10 million people worldwide. Dopamine replacement treatments provide only a symptomatic benefit. No cures or disease modifying therapies for PD exist and this is partially due to lack of predictive animal models. For complex reasons, most mouse or rat genetic models do not reproduce the cardinal pathological features of human PD. Animal models that lack critical pathology are not unique to PD, but has plagued the neurodegenerative field in general, including Alzheimer s disease (AD). Remarkably, Dr. Carol Colton s laboratory (co-mentor) has shown that by humanizing the mouse immune system that AD mouse models demonstrate characteristic AD-like pathologies, thus overcoming significant barriers in AD preclinical research. It is now abundantly apparent that mouse vs. human immune differences are a significant obstacle when testing the mechanistic underpinnings of disease and when translating data from mice to humans. This is largely due to a critical species-based difference in the regulation of nitric oxide synthase (NOS2). Applying these same principles, we have generated a novel transgenic PD mouse that will be used to test gene-environment interactions. Research Applicability and Impact We anticipate pathologic and behavioral characteristics of this new mouse strain will mimic more closely the phenotypes found in human PD. Better preclinical research tools will provide an opportunity for identifying underlying mechanisms, clinically relevant points in the disease course to intervene therapeutically for discovering disease-modifying therapies and ultimately translating greatly needed treatments for clinical development. PI Career Goals, Mentorship, and Development Plan Career goals Although I have expertise in neurodegeneration, DNA repair, and mitochondrial function, I require additional mentoring and training in inflammation and neuroinflammation, which is a key player in PD, especially with regards to LRRK2 function – a major focus of my lab. The training is this award will give me the skills needed to study mechanisms of inflammation in order to bring new novel tools and concepts to our research program. Overall, I have shown the initiative to establish new areas of research in my graduate and postdoc labs, and intend to continue in my own laboratory to integrate novel and cutting-edge concepts and methods into our work. My diverse background places me in an excellent position to pursue innovative paths for understanding the underlying mechanisms of PD. Mentorship The candidate PI will be mentored by Drs. Malu Tansey and Carol Colton. Their collective expertise in neurodegenerative diseases, neuroinflammation, peripheral immune responses, LRRK2 and protein aggregation contribute to the success of this project. Both mentors will ensure that (1) described training was accomplished, (2) project milestones have been met, and (3) career development goals have been achieved. Development Plan The development plan includes learning additional research skills, formal training, participation in journals clubs and scientific meetings locally and nationally, programs offered by the Office for Faculty Development at Duke University, an advisory committee – all in the context of a supportive institutional environment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010687
Entities
People
- Laurie Sanders
Organizations
- Duke University
- United States Army