Thomas Edward Taylor-Clark

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Pain and Nociception

Active NIH awards

• Mechanisms underlying stretch-evoked activation of esophageal vagal afferents

  1R01DK141890-01

  NIDDK · FY 2025 · $595K

  Stretch-sensitive esophageal vagal afferent nerves provide essential sensory feedback to brainstem interocep- tive and motor circuits that control swallow and esophageal peristalsis. Dysfunctional control causes dysphagia, ineffective motility, excessive reflux, and pain. Dysphagia is a risk factor for aspiration pneumonia in neurological and neuromuscular diseases; and excessive reflux causes heartburn in 20% of the US population, one third of which are refractory to therapy. Although the mechanosensitivity of esophageal vagal afferents has been char- acterized into low threshold and high threshold mechanoreceptor fibers, there is a fundamental gap in our un- derstanding of the receptors and/or ion channels responsible for mechanotransduction, action potential (AP) initiation and conduction in esophageal afferents. This significantly hinders our understanding of an essential physiological process in health and disease, prevents rational therapeutic targeting of its components in esoph- ageal dysfunction, and conceals serious esophageal side-effects for future therapies targeting excitability in pain, cough and epilepsy. This gap is due to two reasons: previous mechanosensitive channels have been shown to play limited roles, but Piezo channels have not been tested; and most studies of voltage-gated Na+ channels (NaV1s) required for vagal APs have focused on the cell body with its overwhelming NaV1.7 currents, rather than at the peripheral terminal or axon, thus have overlooked essential roles of NaV1.1, 1.2, 1.6 and 1.8. Our long- term goal is to exploit mechanisms of afferent feedback to improve function in esophageal disorders. The objec- tive here is determine the mechanosensitive channels and NaV1s responsible for transducing esophageal stretch into vagal afferent activation. Our central hypothesis is that stretch-evoked afferent activation is dependent on afferent Piezo channels, whose activation induces AP initiation at the esophageal peripheral terminal and AP conduction within vagal axons via unique interactions of multiple NaV1s. In Aim 1, we will identify the mechani- cally-sensitive receptors required for stretch-evoked activation of esophageal vagal afferents. Our data shows that Piezo2 and Piezo1 are required for mechanotransduction in these afferents. In Aim 2, we will determine the NaV1 channels required for the transduction of mechanical stretch into the initiation of AP from esophageal vagal afferent terminals. Our data shows that AP initiation depends on a combination of NaV1.1, 1.2, 1.6 and 1.7, via non-redundant cooperation with NaV1.8. In Aim 3, we will determine the NaV1 channels required for AP conduc- tion in esophageal vagal axons. Our data shows that NaV1.2, 1.6 and 1.7 cooperate with NaV1.8 in a frequency- dependent manner. Our technical innovations allowing for the study of AP terminal initiation and axonal conduc- tion separately were essential in the development of novel concepts of location-specific NaV1 isoform contribu- tions and of functional cooperation between NaV1.8 and other isoforms. This study will identify the ion channels responsible for the transduction of esophageal stretch into afferent activity, a process essential for life, provide targets for esophageal dysfunction and provide esophageal context for targeting excitability in other diseases.

• Sensory neuronal mechanism for development of house dust mite induced airway hyperreactivity

  1R01HL168051-01A1

  NHLBI · FY 2025 · $387K

  Asthma is the most common chronic inflammatory disease of the airways, affecting 24.6 million people in the US and almost 500 million worldwide. Asthmatic patients have three main characteristics: airway resistance due to narrowing of the airways, lung inflammation, and airway hyperreactivity (AHR). AHR is the excessive and inappropriate response of the airways to a bronchospastic/irritant stimulus. Current asthma medications target airway blockage and inflammation, but none adequately treat AHR. AHR is the cause of most symptoms and exacerbations of asthma and persists even if the chronic inflammation in the lungs is cleared. There is a significant gap in our understanding of the mechanisms underlying the development of AHR. House dust mites (HDM), a common trigger of asthma, cause the development of AHR and evidence suggests this is independent of IgE-mediated atopy and we found this AHR is dependent on nociceptive sensory nerves innervating the airways. However, the mechanisms and specific sensory neve populations responsible for HDM-mediated AHR are poorly understood. The long-term goal of this proposal is to define the neural mechanisms that are triggered by HDM by activating the airway afferents leading to the development of AHR, so that we can develop targeted therapies. The objective of the study is to identify the specific nerve subtype and the signaling mechanism triggered by HDM activation of the airway vagal afferents and determine the mechanism by which AHR eventually develops. The central hypothesis is that HDM component proteases cause PAR1 dependent activation, via TRPV1 and Ano1 ion channels, of vagal C-fibers which leads to the development of HDM-induced AHR. To address the hypothesis, we have three specific aims: Aim 1: Determine the protease-mediated mechanism of HDM-evoked airway afferent activation and AHR. Aim 2: Determine the afferent effectors underlying HDM- mediated afferent activation and AHR. Determine the contribution of chronic activation and phenotypic changes in afferents to HDM-evoked AHR. We hypothesize that the development of HDM-induced AHR in mice is due to the activation of the TRPV1 and Ano1 ion channels, expressed on airway vagal afferents, downstream of PAR1 activation. The rationale of this proposal is that once we understand the mechanisms, we will be able to treat AHR. This R01 will be significant because it this proposal will be the first to define the afferent subset and the molecular mechanisms necessary for triggering AHR in a translationally relevant HDM mouse model of AHR. This R01 research proposal is innovative because it (1) investigates the initial responses to HDM that are sufficient to cause AHR independent of inflammation, (2) hypothesis that HDM components directly activate naïve airway afferents which then lead to AHR, is innovative. The outcomes of this study will provide a novel rationale for pharmacological or electroceutical therapies that target airway afferent nerves hence treating the condition, for the first time, of AHR in clinical studies.

Earlier awards

• Remodeled airway irritant reflexes as a cause of serious cardiovascular eventsFY 2024 · $518K
• Remodeled airway irritant reflexes as a cause of serious cardiovascular eventsFY 2023 · $529K