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Principal Investigator: Tu, Yaping
Institute Receiving Award Creighton University
Location Omaha, NE
Grant Number R21ES029566
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Apr 2019 to 31 Mar 2022
DESCRIPTION (provided by applicant): Early-life environmental cigarette smoke (ECS) exposure alters airway innervation and increases the incidence of asthma later in life, but the mechanisms remain undefined. We recently identified neuronal P-Rex1 as an important regulator of airway innervation and its expression was markedly down-regulated in mice exposed to early-life ECS. Objective: To define the mechanism and importance of P-Rex1 repression in early-life ECS- induced airway hyperinnervation and hyperresponsiveness (AHR), the pathophysiologic hallmark of asthma. Long-term goal: to determine whether targeting neuronal P-Rex1 provides a new strategy for preventing early-life ECS-related asthma progression. Findings: 1) P-Rex1 is highly expressed in neurons but not airway cells. 2) P-Rex1 knockout (KO) mice exhibit airway smooth muscle (ASM) hyperinnervation and AHR. WT mice exposed to early-life ECS showed similar phenotypes with 60% reduction of P-Rex1 in vagal ganglia. Severing vagus nerves attenuated AHR of these mice. 3) ECS exposure enhances brain-derived neurotrophic factor (BDNF) secretion from ASM cells, serving as a target-derived signal for neurite growth of mouse vagal sensory neurons in vitro. 4) P-Rex1 over-expression blocked BDNF-stimulated neurite growth whereas loss of P-Rex1 markedly sensitized these neurons to BDNF stimulation. 5) ECS-elevated interleukin (IL)-6 down-regulates P- Rex1 and enhances BDNF-stimulated neurite growth that is blocked by a PKC inhibitor. Hypothesis: IL-6 repression of neuronal P-Rex1 plays a crucial role in early-life ECS-induced ASM hyperinnervation and AHR of asthma. We will test this hypothesis using molecular, cellular, and animal models. Aim 1: To elucidate the mechanism of early-life ECS-exposure-induced neuronal P-Rex1 repression. We hypothesize that IL-6 represses neuronal P-Rex1 via a PKC-dependent mechanism. We will first use siRNAs to silence P-Rex1 in mouse vagal sensory neurons to assess the importance of P-Rex1 in IL-6 potentiation of BDNF-induced neurite growth. We will then investigate if restoration of P-Rex1 expression attenuates IL-6 stimulatory effects. Finally, we will use inhibitors and siRNAs to identify the PKC isoforms responsible for IL-6-induced P-Rex1 repression and neurite growth. Aim 2: To investigate the pathologic importance of neuronal P-Rex1 repression in early-life ECS exposure-related asthma. We hypothesize that IL-6 repression of neuronal P-Rex1 is a critical determinant in the development and severity of early-life ECS-related asthma. WT and P-Rex1 KO mice will be exposed to ECS or air for 10 days beginning on postnatal day (PND) 2. AHR will be assessed by invasive tracheostomy 24h after a re-exposure of mice to acute insult of ECS or allergen house dust mite on PND59. Effects of early-life ECS exposure on ASM innervation and phenotype (remodeling, contractility) will be examined. Whether loss of P-Rex1 exacerbates early-life ECS-induced ASM hyper-innervation and AHR will be determined. Finally, we will determine whether oral administration of IL-6 inhibitor LMT-28 ameliorates early-life ECS-induced mouse AHR by preventing P-Rex1 repression and ASM hyperinnervation.
Science Code(s)/Area of Science(s) Primary: 69 - Respiratory
Publications See publications associated with this Grant.
Program Officer Frederick Tyson
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