Our goal is to determine how environmental stressors influence the risk and severity of complex diseases, including neurodevelopmental disorders, asthma, Alzheimer’s disease and seizure disorders. Altered patterns of neuronal connectivity and persistent neuroinflammation are associated with neurological deficits. Therefore, we are investigating how environmental contaminants, chemical convulsants and inflammatory mediators trigger neuroinflammation and/or perturb neuronal connectivity as determined using biochemical, morphometric, electrophysiological and behavioral endpoints. We are also developing biomarkers of neurotoxicity and testing novel therapeutic approaches for protecting against the neurodegenerative effects associated with acute intoxication with seizurogenic chemical threat agents. Current funded projects in the lab include:
Neurodevelopmental disorders (NDD): The Lein lab has a long history of research investigating factors that influence development of the peripheral and central nervous system. Our lab has made significant contributions to understanding the role of bone morphogenetic proteins (BMPs) and pro-inflammatory cytokines in regulating axonal and dendritic growth in sympathetic neurons as well as hippocampal and cortical neurons. We have also investigated the effects of biological sex, drugs (statins) and environmental chemicals [the organophosphorus pesticide chlorpyrifos, polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs)] on dendritic arborization, both in primary neurons grown in culture and in the developing brain of rodent models. Our studies with PCBs led to the identification of specific calcium-dependent intracellular signaling pathways that map onto NDD risk genes [Collaborator: Isaac Pessah]. We currently have funding to investigate the role of the microbiome in the developmental neurotoxicity of PCBs [collaborative project with Hans Lehmler and Julia Ciu] as well as the influence of xenobiotic metabolism on neurodevelopmental outcomes associated with developmental exposures to lightly chlorinated PCBs, a subset of PCBs for which there is currently very limited toxicological data [collaborative project with Hans Lehmler and Xinxin Ding].
The CounterACT Center (hyperlink to CounterACT webpage): The goal of the CounterACT Center is to develop more effective medical countermeasures for treating individuals acutely intoxicated with chemical threat agents that trigger seizures. The Lein lab is particularly focused on developing therapeutic strategies for protecting the brain from the neurodegenerative effects associated with chemical-induced status epilepticus. As part of this work, we are collaborating with the Center for Molecular and Genomic Imaging (hyperlink to CMGI) to develop quantitative MRI and PET tracers for longitudinally tracking neuropathology and therapeutic effects of candidate countermeasures in rodent models. This work is a collaborative effort with the laboratories of Michael Rogawski, Isaac Pessah, Heike Wulff, Bruce Hammock, Daniel Tancredi, Abhijit Chaudhari, Joel Garbow, Jill Silverman, Danielle Harvey].
Alzheimer’s disease (AD): This is a relatively new focus for the Lein lab and we have several ongoing projects in which we are leveraging a unique transgenic rat model of AD to investigate a number of different questions. (1) Is traffic-related air pollution (TRAP) an environmental risk factor for AD? If so, what component(s) in TRAP increase risk for AD phenotypes and how? [Collaborators: Tony Wexler, Keith Bein, Jill Silverman, Laura Van Winkle, Fred Gorin]. (2) What is the influence of diet on the rate of onset or symptom severity of AD? [Collaborators: Ameer Taha and Jon Ramsey]. (3) What is the role of senescent endothelial cells and neuroinflammation in the pathogenesis of AD? [Collaborators: Anne Knowlton, Angie Gelli, Fred Gorin]. (4) Are PET tracers that label synapses or neuroinflammation more predictive of early stages of AD than PET tracers for amyloid plaques and neurofibrillary tangles? [Collaborator: Abhijit Chaudhari].