Voice disorders are common in the elderly and have a significant impact on communication and quality of life. Age-related dysphonia has been attributed to a disruption in the normal balance of extracellular matrix turnover. Specifically, the process of protein synthesis and degradation becomes less efficient, resulting in both qualitative and quantitative changes in the deposition of collagen and elastin within the aged vocal fold. Our preliminary studies have also revealed deficiencies in the expression of hyaluronan synthase -1, -2, and -3, genes that code for hyaluronan, an important component of the extracellular matrix and key factor in the regulation of tissue remodeling. Unfortunately, prevailing treatments for the aged vocal fold serve as temporary space fillers, without addressing underlying changes in extracellular matrix gene expression. Our long-term goal is to develop treatments that target gene expression mediated synthesis and degradation of the aged vocal fold. The goal of this R21 exploratory and developmental research is to explore the use of growth factors for restoring the delicate balance among extracellular matrix components in the aged vocal fold. These growth factor treatments are currently being reconstituted and refined in our laboratory, and have imminent potential for the treatment of various disorders of the vocal fold extracellular matrix. During this two- year R21 project period, we will focus on recombinant human hepatocyte growth factor (rhHGF) for enhancing turnover of the aged vocal fold. We provide preliminary data demonstrating proof of concept that rhHGF can be used to stimulate synthesis of the extracellular matrix in-vivo using a setting (vocal fold injury), where we know extracellular hyaluronan to be reduced from our previous studies. We then present data showing reduced expression for genes coding hyaluronan and other extracellular matrices in the aged vocal fold, and provide a foundation from which to explore the use of rhHGF to target synthesis and degradation of the aged vocal fold. We hypothesize that: 1) rhHGF upregulates extracellular hyaluronan in the aged vocal fold via induction of genes coding hyaluronan synthase. We further hypothesize that: 2) rhHGF downregulates collagens and elastin in the aged vocal fold through upregulation of matrix metalloproteinase and suppression of tissue inhibitor of metalloproteinase gene expression. We will test our hypotheses using a prospective, sham-controlled animal design to investigate rhHGF treatment of the aged-vocal fold on gene expression using real-time polymerase chain reaction, direct quantification of tissue matrix using high performance liquid chromatography and enzyme-linked immunosorbent assays, and confirmation of spatial changes using immunohistochemistry.

Public Health Relevance

Voice disorders are common in the elderly and have a significant impact on communication and quality of life. Age-related dysphonia has been attributed to a disruption in the normal balance of extracellular matrix turnover. The goal of this research is to explore the use of growth factors for restoring the delicate balance among extracellular matrix components in the aged vocal fold.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DC009873-02
Application #
7743730
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Shekim, Lana O
Project Start
2008-12-04
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
2
Fiscal Year
2010
Total Cost
$134,274
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Suehiro, Atsushi; Wright, Harry; Rousseau, Bernard (2011) Optimal concentration of hepatocyte growth factor for treatment of the aged rat vocal fold. Laryngoscope 121:1726-34
Ohno, Tsunehisa; Hirano, Shigeru; Rousseau, Bernard (2009) Age-associated changes in the expression and deposition of vocal fold collagen and hyaluronan. Ann Otol Rhinol Laryngol 118:735-41
Ohno, Tsunehisa; Yoo, Mi Jin; Swanson, Erik R et al. (2009) Regeneration of aged rat vocal folds using hepatocyte growth factor therapy. Laryngoscope 119:1424-30
Ohno, Tsunehisa; Yoo, Mi Jin; Swanson, Erik R et al. (2009) Regenerative effects of basic fibroblast growth factor on extracellular matrix production in aged rat vocal folds. Ann Otol Rhinol Laryngol 118:559-64