Parkinson's disease (PD) is a complex progressive neurological disorder best known for the problems it causes in movement and walking. However, while these motor symptoms are the result of degeneration of neuronal cells in the brain, there are also non-motor symptoms that are caused by loss of function of cells outside the brain, called peripheral autonomic neurons. The autonomic nervous system is responsible for the functioning of the heart, bladder, intestines, and blood vessels. In fact, almost 90% of PD patients will develop gastrointestinal problems (constipation, bacterial overgrowth syndrome, weight loss, and gastroparesis) prior to the onset of motor symptoms. Cardiovascular symptoms (orthostatic hypotension, postprandial hypotension, supine hypertension, and non-dipping) are also very common in early-stage PD patients (> 30%) and lower the quality of life for PD patients, even before other symptoms begin. Autonomic nervous system problems are associated with psychiatric disorders and are very challenging to manage, since there are currently no satisfactory treatments.

The lack of relevant experimental models is a strong contributor to the difficulties in exploring the basic biology of autonomic neurons in PD. To bridge this gap in knowledge, I have recently used stem cell technology to generate and characterize functional human autonomic neurons in a dish. I now aim to utilize this novel platform to identify, characterize, and functionally interrogate PD-associated alterations in autonomic neurons following exposure to environmental toxins and pathological aggregate-prone proteins. Any relevant changes can then be used as a "biomarker" to monitor PD risk factors during occupational and environmental exposure to possible toxins. This is highly relevant to prediction and early diagnosis of PD, since autonomic dysregulation is a key early sign of the disease. Identifying the early changes may also provide information about treatment, which can then relieve the non-motor symptoms and improve the patient's quality of life. Almost 90% of PD patients who suffer from non-motor symptoms may ultimately benefit from this work. This study therefore has the potential to affect mission readiness for active-duty military, Veterans, and other military beneficiaries.

I am an Assistant Professor at Tel Aviv University. This award will allow me to advance my career at the front of PD research by: (a) providing me with the opportunity to be the first to identify and modulate vulnerabilities of autonomic neurons associated with PD and neurotoxin-exposure; (b) allowing me to expand the experimental methodologies used in my lab; and (c) enable me to deepen my professional relationships with leaders in the field of PD. The Career Guide proposed for this project is Dr. Clive Svendsen, the director of the Regenerative Medicine Institute at Cedars-Sinai and a world-renowned scientist in modeling and treating PD using stem cell technology. I expect to benefit considerably from my interactions with Dr. Svendsen.