The patient with acute recurrent laryngeal nerve (RLN) injury suffers not only the functional consequences of impaired vocal fold motion, but also the psychological impact of reduced communication. Patients with unilateral RLN injury are variably disabled by aphonia and aspiration, while bilateral RLN injuries obstruct the airway, thereby necessitating tracheotomy. These conditions are often the direct result of inappropriate reinnervation of laryngeal muscles by axons that are misdirected in the course of regeneration. The process of reinnervation is influenced by surface molecules that promote cell adhesion. Ideally, this process should simulate the normal developmental process wherein axon-axon and axon- muscle connections are made correctly. When proper connections fail to develop, residual laryngeal weakness and impairment of function occur. The purpose of this study is to define the cellular changes in motor unit organization responsible for observed patterns of RLN reinnervation of the rat laryngeal musculature. The proposed study continues earlier work which suggests that patterns of laryngeal reinnervation are subject to preferential contact of the laryngeal muscles by adductor motoneurons of the nucleus ambiguus. To further evaluate the process of laryngeal reinnervation in the rat model, regenerating motoneurons will be classified according to their original function using retrograde labeling techniques. Cell number and somatic size will be correlated with metabolic alterations associated with nerve injury using histochemical assays for succinic dehydrogenase and cytochrome oxidase. Immunocytochemistry techniques will be employed to evaluate the role of cell adhesion molecules in the process of reinnervation, specifically addressing expression with respect to laryngeal motoneuron and muscle function. Patterns of cell adhesion molecule expression in repair will be compared to the events occurring in the normal developing central and peripheral nervous system. This CIDA application is based on the proposed studies and advanced training in developmental neurobiology, immunocytochemistry, electron microscopy and biostatistics. The basic training is intended to develop an applied research program focused on laryngeal development and mechanisms of RLN regeneration.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Clinical Investigator Award (CIA) (K08)
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Communication Disorders Review Committee (CDRC)
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Johns Hopkins University
Schools of Medicine
United States
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Flint, Paul W; Nakagawa, Hideki; Shiotani, Akihiro et al. (2004) Effects of insulin-like growth factor-1 gene transfer on myosin heavy chains in denervated rat laryngeal muscle. Laryngoscope 114:368-71
Shiotani, A; Nakagawa, H; Flint, P W (2001) Modulation of myosin heavy chains in rat laryngeal muscle. Laryngoscope 111:472-7
Shiotani, A; Westra, W H; Flint, P W (1999) Myosin heavy chain composition in human laryngeal muscles. Laryngoscope 109:1521-4
Shiotani, A; O'Malley Jr, B W; Coleman, M E et al. (1999) Human insulinlike growth factor 1 gene transfer into paralyzed rat larynx: single vs multiple injection. Arch Otolaryngol Head Neck Surg 125:555-60
Flint, P W; Shiotani, A; O'Malley Jr, B W (1999) IGF-1 gene transfer into denervated rat laryngeal muscle. Arch Otolaryngol Head Neck Surg 125:274-9
Shiotani, A; Jones, R M; Flint, P W (1999) Postnatal development of myosin heavy chain isoforms in rat laryngeal muscles. Ann Otol Rhinol Laryngol 108:509-15
Shiotani, A; O'Malley Jr, B W; Coleman, M E et al. (1998) Reinnervation of motor endplates and increased muscle fiber size after human insulin-like growth factor I gene transfer into the paralyzed larynx. Hum Gene Ther 9:2039-47
Shiotani, A; Flint, P W (1998) Myosin heavy chain composition in rat laryngeal muscles after denervation. Laryngoscope 108:1225-9
Shiotani, A; Flint, P W (1998) Expression of extraocular-superfast-myosin heavy chain in rat laryngeal muscles. Neuroreport 9:3639-42
Flint, P W; Corio, R L; Cummings, C W (1997) Comparison of soft tissue response in rabbits following laryngeal implantation with hydroxylapatite, silicone rubber, and Teflon. Ann Otol Rhinol Laryngol 106:399-407