sympathetic

Cardiorespiratory and autonomic impacts of coolants in e-cigarette aerosols

PROJECT SUMMARY / ABSTRACT Coolants such as menthol, WS-3, and WS-23 are widely used in electronic cigarettes (e-cigs) to reduce irritation and enhance appeal—especially among youth. Despite their prevalence, the cardiopulmonary toxicity of these agents remains poorly characterized. Recent work shows that e-cig aerosols can disrupt autonomic nervous system regulation and cardiac electrophysiology, increasing catecholamine release, enhancing sympathetic regulation of cardiac rhythm, and provoking arrhythmias. Proof is also mounting that nicotine’s sympathomimetic traits mediate these pathogenic effects. Preliminary data from our laboratory show that coolants increase systemic nicotine levels, blunt respiratory reflexes, and potentiate arrhythmias upon exposures to e-cigarette aerosols, suggesting a paradoxical role for coolants in suppressing ventilatory responses while intensifying cardiovascular risk. These findings take on added significance in light of recent case reports of sudden cardiac arrest in young e-cigarette users, including some in otherwise healthy individuals. This project will elucidate how e-cigarette coolants alter exposure to harmful and potentially harmful constituents (HPHCs)—particularly nicotine and aldehydes—concurrent with their effects on cardiovascular and respiratory physiology. Using robust murine models with continuous ECG, blood pressure, and pleural pressure telemetry, we will assess how coolants alter the acute and chronic effects of e-cigarette aerosols on cardiac electrophysiology, autonomic tone, ventilatory function, hemodynamics, and toxicant exposure. We will also evaluate how coolant concentration and device power modulate these effects. In parallel, we will determine whether adolescent mice exhibit heightened susceptibility to these effects compared to adults, with attention to sex differences and the persistence of cardiotoxicity after exposure cessation. This comprehensive, multi-modal approach incorporates novel protocols for arrhythmia inducibility, high-resolution physiologic monitoring, and complementary analyses of biomarkers of exposure and effect. By clarifying how coolants interact with HPHCs—especially nicotine and aldehydes—to drive cardiopulmonary injury across age and sex, this work addresses high-priority research areas identified in RFA-OD-25-001, including the toxicological evaluation of e-cigarette constituents and their cardiopulmonary effects. The results will inform regulatory policy and public health strategies aimed at mitigating cardiovascular risk associated with e-cigarette use, particularly among vulnerable youth.

Effects of Apolipoprotein A4 on Lipid Metabolism via Sympathetic Regulation

Obesity increases the risks and progression of hypertriglyceridemia, metabolic dysfunction- associated steatotic liver disease (MASLD), and cardiovascular diseases. Previous studies demonstrate that a single injection of apolipoprotein A4 (APOA4) elevates sympathetic neural activity and fatty acid β-oxidation in adipose tissues; and consistent infusion of APOA4 in obese mice fed a high-fat diet lowers fat mass, reduces hypertriglyceridemia, elevates brown adipose tissue thermogenesis, and attenuates steatosis and enhances sympathetic neural activity in the liver. This project hypothesizes that APOA4 reduces hypertriglyceridemia by regulating lipid metabolism through sympathetic stimulation in adipose tissues (Specific Aim 1) and sympathetic action in the liver (Specific Aim 2). The role of sympathetic action via the neurotransmitter norepinephrine and adrenergic receptor-mediated pathways will be investigated, and their necessity in APOA4-mediated lipid metabolism will be tested. A strength of this project is the interdisciplinary collaboration between investigators with established successful collaboration and publications. The project will provide physiological, molecular, and neurochemical mechanisms underlying how APOA4 differentially regulates metabolism through sympathetic activation in various types of adipose tissues and the liver in male and female obese mice. Findings would provide impetus to develop unique, novel, targeted therapeutic applications against hypertriglyceridemia and MASLD. Importantly, this project will expose undergraduates and graduate students to meritorious research, provide students with hands-on biomedical research experience, and strengthen research environment at R15 eligible institutions.

AI-guided structural biology of Cav1.2

Project Summary/Abstract The L-type calcium channel Cav1.2 plays a critical role in excitation-contraction coupling in the heart. Its calcium flux generates the plateau phase of the cardiac action potential and results in the calcium-induced calcium release needed to trigger cardiac contractions. Cav1.2 is a multi-subunit protein consisting of a large, transmembrane 1 subunit and smaller, auxiliary subunits important for trafficking and channel regulation. Recent cryogenic electron microscopy (cryo-EM) experiments have revealed much of the three-dimensional structure of Cav1.2’s core domains, though the final 571 residues of the 1 subunit’s intracellular C-terminal domain (CTD) have not yet been resolved despite key regulatory roles in channel function. This domain has been shown to be important for Cav1.2’s regulation by calcium/calmodulin and has an important role in cross- talk between Cav1.2 and the sympathetic nervous system, amongst other cell signaling pathways. In this proposal, I will use insights from artificial intelligence to develop a platform for CTD structural biology, then validate that platform by measuring its ability to form protein-protein interactions with known binding partners of Cav1.2, including calcium/calmodulin and an autoregulatory distal C-terminal fragment. If successful, I will also attempt crystallization of the CTD in complex with several binding partners. Together these data will provide the starting point for future structural biology projects on Cav1.2 regulation and protein-protein interactions.

Clonal analysis at single cell level helps to understand neural crest development

Recent research on the neural crest has revealed the multipotency and plasticity of nerve-associated Schwann cell precursors, which can differentiate into diverse cell types, including parasympathetic neurons, neuroendocrine cells, and mesenchymal stem cells. These findings challenge the traditional view of peripheral nerves, highlighting their role as niches for migratory progenitor cells that contribute to tissue formation and regeneration.

Sympathetic nerve remodeling in adipose tissue

Sympathetic nerve activation of adrenergic receptors on fat is the major pathway the brain uses to drive non-shivering thermogenesis in brown adipose tissue and lipolysis in white fat. There is accumulating evidence that the peripheral nerve architecture inside of organs is plastic (can be remodeled) but the factors and conditions that regulate or result in remodeling are largely unknown. Particularly for fat, it remains unclear if nerves in fat can be remodeled in step with hyperplasia/trophy of adipose tissue as result of a prolonged energy surfeit. This talk will discuss our recent work identifying the sympathetic nerve architecture in adipose tissue as highly plastic in response to the adipose hormone leptin, the brain circuitry leptin acts on to regulate this and the physiological effects remodeling of innervation has on fat tissue function.

Sympathetic control of lymph node function

Peripheral nerve injury can cause debilitating disease and immune-cell mediated destruction of the affected nerve. While the focus of most studies has been on the nerve-degenerative response, the effect of loss of innervation on lymph node function is largely unclear. Here, I will discuss the cellular and molecular events caused by local denervation and loss of direct neural input to the popliteal lymph node that induce an inflammatory response and lymph node expansion.

Untitled Seminar

Sympathetic Associated Perineurial Cells (SAPCs) orchestrate neuroendocrine loop of leptin action to maintain metabolic homeostasis

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

Functional characterization of human induced pluripotent stem cell-derived sympathetic neurons

FENS Forum 2024

Psychological stress regulation of acute-phase proteins through the hepatic sympathetic innervation

FENS Forum 2024

Sympathetic neural-immune interactions involved in early life stress-induced gastrointestinal disorder

FENS Forum 2024