An exciting, new investigative theme in airway physiology and pathophysiology is neurotrophins (NTs): growth factors including brain-derived neurotrophic factor (BDNF) known for their diverse roles in the nervous system. NTs and their receptors have now been found in different lung components including airway smooth muscle (ASM), with altered expression observed in asthma, allergy, and even lung cancer. While NTs may be derived from several sources, our published and preliminary data suggest that ASM is a target of NTs, and that NTs contribute not only to ASM contractility under normal circumstances, but also to increased contractility with airway inflammation (such as that induced by TNFa). The long term goal of the proposed studies is to understand the role of NTs in ASM physiology and pathophysiology. The overall hypothesis is that NTs enhance a) sarcoplasmic reticulum (SR) Ca2+ release and Ca2+ influx;and b) Ca2+ sensitivity for force generation in ASM. We propose that BDNF is a key NT influencing ASM contractility. Finally, airway inflammation enhances BDNF signaling, leading to an overall enhancement of [Ca2+]i and force. In this proposal, we will use human ASM and the ovalbumin (OVA) mouse model to examine the relative role of the BDNF receptors (high affinity TrkB vs. low affinity p75NTR) vis-?vis ASM contractility. We hypothesize that TrkB is more important for [Ca2+]i regulation, while p75NTR regulates force. Using biochemistry, pharmacology, molecular biology, immunocytochemistry, fluorescence Ca2+ imaging, force measurement techniques, and lung mechanics, we will focus on specific mechanisms that may be regulated by BDNF: the second messengers IP3 (via phospholipase C PLC) and cyclic ADP ribose (via CD38) (Aim 1);SR Ca2+ release (IP3 receptor vs. ryanodine receptor (RyR) channels) (Aim 2);Ca2+ influx via store-operated Ca2+ entry (SOCE) (Aim 3) and the force regulatory mechanisms myosin light chain (MLC20) and rhoA/rho-kinase (Aim 4). These in vitro studies in human ASM will be integrated into the OVA mouse model applied in focus studies to the TrkB knockin mouse (where TrkB functionality is reversibly inhibited). We will explore the idea that inflammation induced by TNFa increases constitutive BDNF receptor expression, and alters specific [Ca2+]i and force regulatory mechanisms, thus priming ASM for enhanced response to both BDNF and bronchoconstrictor.
The Specific Aims are:
Aim 1 : To determine mechanisms by which BDNF modulates second messenger signaling in human ASM;
Aim 2 : To determine mechanisms by which BDNF modulates SR Ca2+ regulation in human ASM;
Aim 3 : To determine mechanisms by which BDNF modulates SOCE in human ASM;
Aim 4 : To determine mechanisms by which BDNF modulates force regulation in human ASM;
Aim 5 : To determine the role of BDNF in ASM contractility in a mouse model of airway inflammation and hyperresponsiveness.
. There is increasing recognition that abnormalities in airway smooth muscle contractility (exacerbated by inflammation) contribute to exaggerated airway narrowing and accompanying shortness of breath in clinically important diseases such as asthma and chronic bronchitis. In this regard, the potential role of growth factors called neurotrophins in regulation of airway contractility is an exciting and emerging area of research. By establishing the role of neurotrophins in airway narrowing with or without inflammation, the proposed studies will the foundation for better understanding of airway diseases, and potential development of new therapeutic targets.
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