2016 — 2017 |
Jordt, Sven-Eric |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Mechanisms of Itch in Poison Ivy-Induced Allergic Contact Dermatitis
Allergic contact dermatitis (ACD) is a common skin condition triggered by environmental or occupational allergens. In the US, the most common ACD is caused by contact with poison ivy with at least 10 million cases each year. Exposures to poison ivy have increased in recent years due to accelerated growth of the plants, increased production of allergens, and the spread of poison ivy to northern states, all of which are likely due to the increase in atmospheric carbon dioxide levels associated with climate change. The major clinical manifestations of poison ivy-induced ACD are skin rashes, swelling, and intense and persistent itch (pruritus), followed by the appearance of vesicles and bullae in severe cases. The severe itch sensation associated with poison ivy ACD triggers scratching behavior that is hard to control, especially in children, and further injures the skin. Antihistamines are generally ineffective for treating the pruritus associated with ACD. Scratching can also lead to skin infections that require antibiotic treatment. It is estimated that 50-75% of Americans are sensitized to urushiol, the primary allergen in poison ivy. However, surprisingly few published studies have explored in detail the pruritus mechanisms involved in poison ivy-induced ACD. Recent studies demonstrated that proinflammatory cytokines and chemokines, such as IL-31, TSLP and CXCL10 are endogenous pruritogens and activate corresponding receptors expressed in primary sensory neurons to produce pruritus. Blocking the signaling pathway of these endogenous pruritogens can effectively reduce pruritus behaviors in mouse itch models. IL-33 is an epithelial cell-derived proinflammatory cytokine, and signals via receptor ST2, which is highly expressed on Th2 cells and various types of innate immune cells. Recent evidence demonstrated the involvement of IL-33 in allergic skin diseases. In our pilot studies, mouse transcriptome microarray showed that IL-33 is significantly increased in the inflamed skin of mice with urushiol- induced ACD. We further found that ST2 receptor is expressed in a subset of dorsal root ganglion (DRG) neurons, including neurons that specifically innervate the skin. Therefore, our central hypothesis is that IL-33 acts via ST2 expressed in peripheral sensory neurons to produce pruritus, and that blocking IL-33/ST2 and other related endogenous pruritic pathways is effective against pruritus caused by urushiol-induced ACD. Successful completion of the work proposed here will 1) establish a link between IL-33 and poison ivy-induced ACD, 2) reveal a previously unrecognized interaction between IL-33 and primary sensory neurons, and 3) identify major pruritogens that cause the intense and persistent pruritus associated with poison ivy-induced ACD. Further, our pilot studies have shown that IL-33 receptor complex (ST2 and IL1R1) transcripts are expressed in human DRGs. Therefore, the proposed studies are highly significant because they are crucial steps toward the development of mechanism-based strategies to effectively treat the severe pruritus of poison ivy-induced ACD.
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2018 — 2020 |
Jordt, Sven-Eric |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Anesthetic and Synthetic Cooling Flavors in E-Cigarettes: Chemistry and Respiratory Effects Modulating Nicotine Intake
SUMMARY The Family Smoking Prevention and Tobacco Control Act (FSPTCA) prohibits the addition of artificial or natural flavors to tobacco cigarettes, with the exception of menthol. While the prohibition of flavored cigarettes in 2009 set in motion a significant decline in youth tobacco use, the proportion of menthol cigarette smokers has increased, suggesting that menthol may promote initation and maintain addiction. Flavor perception results from a synthesis of stimuli carried by gustatory, olfactory and somatosensory nerves. Cooling flavors such as menthol are considered soothing,. TRPM8, a member of the TRP ion channel family, is the target of menthol and other cooling agents in cold-sensing neurons and is also activated by cold temperature. The flavor industry has developed a range of synthetic cooling agents with novel sensory properties. These synthetic cooling agents have been detected in unregulated electronic cigarette liquids and are sold by online vendors as powders or solutions to mix into E-liquids.Other flavorants may also affect properties of sensory systems, including clove flavors, flavored with eugenol, a widely used dental anesthetic, and wintergreen flavors, flavored with methyl salicylate, a topical analgesic. In our preliminary studies we show that synthetic coolants and eugenol strongly activate TRPM8 channels. We performed a chemical analysis of clove-flavored E-liquids, and revealed that some contain very high eugenol levels (>100mM). In mice we observed that menthol reduced respiratory irritation by aldehyde-flavorant containing E-liquids, suggesting that menthol facilitates inhalation. We also observed that menthol increased cotinine levels, suggesting higher nicotine intake. Based on these findings, we hypothesize that some electronic cigarette liquids contain pharmacologically active flavorants that produce vapors with counterirritant or anesthetic effects suppressing respiratory irritation and facilitating initiation of product use. The following specific aims, using analytical chemical, pharmacological and physiological methods, are designed to produce evidence for or against this hypothesis. Aim 1: Determine contents of anesthetic and cooling agents in E-cigarette liquids and condensed vapors Aim 2: Determine pharmacological effects of E-liquids and condensed vapors containing anesthetic or cooling agents on mouse and human irritant receptors and excitability of trigeminal sensory neurons Aim 3: Measure impact of vapor exposure on ventilation and the respiratory irritation response in mice. Due to the close similarities between human and rodent TRP ion channels and their flavorant pharmacology, data resulting from these studies may support efforts to regulate some flavorants as pharmacologically active agents.
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2019 — 2021 |
Achanta, Satyanarayana (co-PI) [⬀] Jordt, Sven-Eric |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Advanced Trpa1 Inhibitor For the Treatment of Chlorine Inhalation Injury
Summary Chlorine gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Despite its devastating effects, no mechanism-based treatment has been developed. In this application, we hypothesize that targeting the TRPA1 ion channel post-exposure will ameliorate the acute pulmonary, cardiovascular and neurological effects of chlorine, leading to decreased morbidity and improved recovery. TRPA1 is a chemical irritant receptor eliciting pain, edema, vasodilation, cardiac arrhythmia, inflammation and leukocyte infiltration. Our preliminary studies in mice show that TRPA1 inhibitors, when administered post-chlorine exposure, prevent the chlorine-induced decline of blood oxygenation, improve pulmonary function and mitigate inflammation. Here, we propose to test the efficacy of a 3rd generation TRPA1 inhibitor, found to block mouse, human and porcine TRPA1, in mouse and pig models of chlorine inhalation injury, with the goal to develop this compound as a future human countermeasure. The following aims are proposed: Aim 1: Screen potential therapeutic effects of a 3rd generation TRPA1 inhibitor in mouse models of Cl2 gas inhalation injury. Aim 2: Determine the pharmacokinetic and toxicological properties of TRPA1 inhibitor in pigs. Aim 3: Test the TRPA1 inhibitor in a pig model of chlorine gas inhalation injury
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2020 |
Jordt, Sven-Eric |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Molecular Core
Molecular Core ? Summary The molecular and immunological characterization of inflammation and injury markers is crucial for the evaluation of the analgesic complementary approaches proposed in all four projects of this Center. Preliminary studies have identified sets of pro-inflammatory genes in sensory ganglia, spinal cord, brainstem and brain strongly induced by the pro-algesic stimuli in the models (chemotherapy, tibial fracture, functional pain syndrome, trigeminal pain) suggesting that pain has detrimental effects on the function of the CNS and induces inflammatory states in other organs remote from the site of injury. The Molecular Core will support the Center Projects through the following Specific Aims: Core Specific Aim 1: Analyze the effects of injuries, prior stress and complementary analgesic interventions on gene expression in injured tissues and neuronal tissues of the pain pathway. Core Specific Aim 2: Determine systemic and tissue levels of inflammatory biomarkers and inflammation-resolving lipid mediators. Core Specific Aim 3: Examine the effects of pain stimuli, prior stress and complementary interventions on systemic leukocyte profiles and neuroinflammatory cells in neuronal tissues. Core Specific Aim 4:Provide resources for production of viral tracers for labeling of neuronal circuits engaged in pain models and by bioelectronic complementary analgesic interventions. Methods include quantitative PCR analysis, multiplex immunoassays and ELISAs, flow cytometry and cell culture. The Molecular Core will work closely together with Project Investigators, Behavioral Core, the Statistical Unit of the Administrative Core and external core facilities to establish a workflow for sample tracing, blinded data transfer and feedback for optimization of experimental designs.
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2020 — 2021 |
Achanta, Satyanarayana [⬀] Jordt, Sven-Eric |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Specialized Pro-Resolving Mediators as Potential Medical Countermeasures in a Pig Model of Chlorine Gas-Induced Acute Lung Injury
Chlorine is a highly utilized chemical in the U.S. with more than 10 million metric tons produced annually for purposes including water treatment, paper bleaching, and chemical manufacturing. Unfortunately, however, chlorine is also a toxic inhalant. Exposure to chlorine gas can cause immediate and sustained injury to the respiratory tract with the severity of injury depends on both concentration and duration of exposure. Whereas exposure to chlorine gas is typically accidental, it has been used as a chemical weapon since World War I. Despite its known chemical threat potencies since World War I, there is no specific antidote for chlorine gas-induced injuries. Recent studies in our laboratory revealed that post-exposure treatment with specialized pro-resolving mediators (SPMs), such as Resolvin D1 and Protectin D1 strongly improved lung injury outcomes in mice exposed to chlorine and hydrochloric acid (HCl). These SPMs are endogenous lipid derivatives produced during inflammation cascade that subsequently accelerates the resolution phase of inflammation. In the proposed grant application, we want to test these novel potential therapeutic agents in our well-established pig model of chlorine gas-induced acute lung injury following the FDA's animal rule.
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