Rahul Srinivasan, M.B.B.S, Ph.D - US grants

In this convergent project, mechanical and biomedical engineers, a nanoscientist, and neuroscientists develop new understanding of how to program magnetic nanorobots to effectively communicate and interact inside networks of neurons. If successful, this may provide a possible approach for non-invasive brain therapeutics. The fundamental analysis of the cellular interaction behavior of magnetic nanorobots may lay a foundation for novel and translatable approaches to treat intractable disorders such as neurodegeneration, epilepsy, chronic pain, and spinal cord injury. Additionally, the research promotes disciplinary integration across nanoscience, mechanical engineering, biomedical engineering, neuroscience and experimental therapeutics. The project provides research experiences for high school teacher and students, undergraduate and graduate students.

The knowledge generated by the convergent effort will form novel frameworks to catalyze scientific discovery and innovation in brain tissue regeneration and repair, and will provide a powerful, scalable and controllable technology of self-driving nanorobots transporting and functioning inside the brain environment. It will also enhance fundamental understanding of long-term changes in the activity of specific neural circuits with degenerative neurons. An explainable artificial intelligence framework provides additional quantitative assays to complement a biologically plausible, continuously remodeling, analytical, microvascular network model. Furthermore, combined with recent advances in power electronics, this project holds a high potential for contributing to the development of a new machine learning model that improves researchers? capacity for studying the growth behavior of neurons inside a 3D extracellular matrix.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Parkinson?s disease (PD) is the second most common neurodegenerative disorder, predicted to affect over 12 million people worldwide by 2040. There is no cure for PD and current treatments are merely symptomatic, which underscores an urgent and unmet need for neuroprotective drugs. One major barrier for the inability to develop effective and clinically translatable neuroprotective drugs is that no single animal model recapitulates the complex process that leads to dopaminergic (DA) neuron loss in PD. Therefore, most drugs that succeed in preclinical animal models fail to work in PD patients. The current proposal addresses this barrier by focusing on hyperactivated endoplasmic reticulum (ER) stress, which is an established convergent mechanism downstream of multiple PD-related toxicities. ER stress consists of three signaling arms that culminate in the translocation of three key proteins ? ATF6, XBP1, and CHOP into the nucleus of DA neurons. Moderate activation of ATF6 and XBP1 is neuroprotective, while chronic, uncontrolled activation of these proteins leads to DA cell death. By contrast, activation of CHOP invariably causes cell death. Experiments showed that the nicotinic compound cytisine causes an upregulation of specialized structures called ER exit sites (ERES), and this is associated with an inhibition of ATF6 and XBP1. Surprisingly, experiments in a 6-hydroxydopamine (6-OHDA)-induced preclinical toxin model of PD showed that cytisine is neuroprotective only in female mice. Additional preliminary experiments showed that 17-?-estradiol inhibits CHOP expression in DA neurons, which fits with strong sex-differences observed in the incidence and phenotype of PD, with men being more prone to developing PD than women. Based on these data, this proposal hypothesizes that cytisine and estrogen exert neuroprotection in female mice by synergistically inhibiting all three arms (ATF6, XBP1 and CHOP) of hyperactivated ER stress in DA neurons. Experiments are proposed to determine the extent to which cytisine requires ERES for exerting neuroprotection by specifically deleting ERES in DA neurons or by using nicotinic compounds that cannot upregulate ERES. Female mice will be ovariectomized to determine mechanisms by which specific subtypes of estrogen receptors exert neuroprotection in female mice. On completing experiments in this proposal, key signaling targets through which cytisine and estrogen mediate neuroprotective effects will be identified. Success in this proposal will lay groundwork for the long-term goal of discovering clinically translatable neuroprotective PD drugs that work in both men and women.