ARRA: Exogenous growth factors for reversal of age-related laryngeal muscle denervation

This application is in response to the NIDCD Research Grants for Translating Basic Research into Clinical Tools for Human Health (R21) (PAR-08-018). As individuals age, muscle weakness and neuromuscular disorders have the potential to diminish the quality of life, increase healthcare costs, and lead to institutionalization. The larynx is part of a complex motor system that serves as a vibratory source of phonation and as a regulator that separates and protects the airway from the digestive tract. In the elderly, age-related changes in the intrinsic laryngeal muscles may compromise voice quality, thus impair the ability to communicate and diminish the ability to remain socially engaged. Laryngeal muscle dysfunction may also cause dysphagia and increase the risk of aspiration, factors that lead to higher mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age. More specifically, the neuromuscular junctions (NMJs) become smaller and less abundant in aging rat laryngeal muscles, and there is evidence of functional denervation. Therefore, this project has two major objectives:( 1) it will test the efficacy of exogenous neurotrophins as treatment to reverse denervation in the aging intrinsic laryngeal muscles; (2) it will provide the background to extends these findings to clinical treatments. The studies will test the central hypothesis that age related laryngeal muscle denervation is corrected by treatment with exogenous neuronal growth factors. Using the Fisher 344-Brown Norway F1 hybrid rat model of aging, the studies will examine to what extent neurtrophins correct NMJ disorganization in the posterior cricoarytenoid (PCA, vocal fold abductor) and thyoarytenoid (TA, vocal fold adductor) muscles. Specific Aim I will examine whether systemic administration of the exogenous neurotrophins brain-derived nerve growth factor (BDNF) and neurotrophin-4 (NT-4) changes determinants of NMJ assembly in the aging PCA and TA. Specific Aim 2 will test whether local infiltration with the two growth factors influences NMJ structure and abundance in the aging PCA and TA muscles. This will be a first test of pharmacological interventions intended to reverse age-related neuromuscular dysfunction in the laryngeal muscles. This project will generate novel data on interventions aimed at preventing or reversing age-related neuromuscular dysfunction in these small muscles, a first step to testing their efficacy in the clinical setting. Project Description