I am pleased to present the President's budget request for the National Institute on Deafness and Other Communication Disorders (NIDCD) for FY 2003, a sum of $371,951,000, which reflects an increase of $28,880,000 over the comparable FY 2002 appropriation. The NIH budget request includes the performance information required by the Government Performance and Results Act (GPRA) of 1993. Prominent in the performance data is NIH's second annual performance report which compared our FY 2001 results to the goals in our FY 2001 performance plan.

Disorders of hearing, balance, smell, taste, voice, speech, and language exact a significant economic, social, and personal cost for many individuals. The NIDCD supports and conducts research and research training in the normal processes and the disorders of human communication that affect many millions of Americans. Human communication research now has more potential for productive exploration than at any time in history. With substantive investigations conducted over the past decades and the advent of exciting new research tools, the NIDCD is pursuing a more complete understanding of the scientific mechanisms underlying normal communication and the etiology of human communication disorders. Results of this research investment will foster the development of more precise diagnostic techniques, novel intervention and prevention strategies, and more effective treatment methods.

Excessive noise has long been recognized as an occupational hazard among adults, and hearing conservation programs have been implemented in the workplace. However, the resiliency of a child's auditory system following noise exposure needs further research. Chronic exposure to loud music, fireworks, lawn mowers or toys can accumulate over a lifetime to gradually produce irreversible damage to the sensory cells of the inner ear. The results of a recent survey conducted by the Centers for Disease Control and Prevention revealed that approximately 5.2 million American youths have some degree of hearing loss due to exposure to noise at hazardous levels.

Identification of Genes Causing Deafness. Hearing loss occurs with a frequency of about 1 in 1,000 newborns and is also a prevalent, but not necessarily inevitable, feature of the aging process. Causes of hearing loss in children and the elderly include viral and bacterial infections, loud noise, head trauma, drugs or other chemicals that are toxic to the sensory cells of the inner ear, as well as mutations in genes critical for normal auditory function and development. NIDCD scientists are identifying the genes whose mutations result in hearing loss. Recently, NIDCD Intramural scientists identified a gene located on chromosome 10 that is involved in Usher syndrome type 1D (USH1D). Individuals that inherit two copies of this mutated gene are born profoundly deaf, have severe balance problems and gradually lose their sight beginning in adolescence. The scientists discovered that USH1D gene encodes a protein called cadherin-23. Knowledge of the function of cadherin-23 in the inner ear will provide new insight into cellular processes essential for normal auditory function, which may ultimately guide the development of improved diagnosis and treatment methods. NIDCD expects to support collaborations between its Intramural scientists and those of the National Eye Institute in these areas.

NIDCD scientists also identified a gene (DFNB29) located on chromosome 21 whose mutation caused recessively inherited hearing loss. This gene encodes a protein, claudin-14, which is believed to help seal adjacent cells together in the inner ear thus preventing the leakage of endolymph fluid. The endolymph bathes the sound transduction cells and is essential for conversion of the mechanical energy of sound into an electrical signal that is sent to the brain. Studies are underway in a new mouse model to advance our understanding of the function of claudin-14.

Discovery of Novel Deafness Genes and Genetic Characterization of Hearing Impairment. NIDCD has developed a substantial research portfolio to study existing mouse mutants as well as creating new mouse models to facilitate the discovery and analysis of genes whose mutation causes hereditary hearing impairment in humans. In a recent study utilizing the mouse mutant Waltzer, NIDCD Intramural scientists showed that mutations in the human cadherin gene family cause Usher Syndrome type 1D. This mouse model is a critical research tool for determining the identification of the mechanisms by which cadherin mutations cause this devastating deafness and blindness syndrome. In another NIDCD-supported study, a mouse nuclear gene has now been shown to interact with mutated genes in the mitochondria to significantly alter the severity of age-related hearing loss. This model system should provide important information regarding age-related hearing loss in humans, a relatively common and debilitating health problem within the aging U.S. population. These findings underscore the power of mouse genetics and the value of mouse models of deafness for the identification and detailed molecular characterization of human hearing impairment.

Scientists Identify Sweet Taste Receptor Gene. Understanding the molecular and cellular events that occur at the early stages of taste perception at the level of the taste receptor cell provides important insight into how we taste different sweet, bitter, salty and sour substances. A variety of distinct signaling pathways are activated by the basic taste qualities of salty, sour (acid taste), sweet, and bitter. Salty- and sour-tasting compounds activate ion channels that are located at taste receptor cells clustered within taste buds of the tongue and palate while bitter and sweet compounds bind to G protein-coupled receptors. Recently, four NIDCD-supported laboratories independently identified a gene, T1R3, at the mouse Sac locus that encodes a sweet taste receptor subunit. Differences in sweetener intake among inbred strains of mice are partially determined by variation in genes at the saccharin preference (Sac) locus. It was determined that the T1R3 receptor differs in amino acid sequence in "sweet preferring" versus "sweet indifferent" mouse strains. Both human and mouse T1R3 are G protein-coupled receptors, and are selectively expressed in subsets of taste receptor cells that are sensitive to sweet substances.

Abilities in Auditory Pitch Recognition are Largely Inherited. Auditory pitch recognition is a complex process that allows us to determine the pitch or tone of a sound. In this process, the ears receive the sound signal and the brain interprets this signal to produce the pitch we perceive. Individuals with problems in pitch recognition are sometimes referred to as "tone deaf." Severe deficits in pitch recognition may be associated with speech and language disorders. It was long known that tone deafness can run in families. However, it was not known whether this disorder was due to inherited genes or to a common environment shared by family members. To answer this question, NIDCD Intramural scientists performed a large study on twins. The results show that identical twins scored much more alike than fraternal twins on a Distorted Tunes Test. The data revealed that approximately 70-80% of an individual's score is due to their genes and 20-30% due to other factors. The discovery that individual differences in pitch recognition are mostly genetic opens up the possibility of using genetic methods and information from the Human Genome Project to find the genes essential for pitch recognition. Identifying such genes and how they function will provide new insight into how the brain processes sound.

How Basic Biology Translates into New Technology to Help the Hearing Impaired. Over the past decade, NIDCD-supported scientists have been studying the amazing auditory capability of Ormia ochracea, a tiny parasitic fly with such acute directional hearing that it has inspired a new generation of hearing aids and nanoscale listening devices. Ormia can detect very small differences in sound-source position, a situation analogous to humans trying to detect who is speaking in a crowded room. This accomplishment is due to the unique anatomy of the eardrums of Ormia. The fly's eardrums are connected internally by a cuticle-based bridge that functions as a flexible lever. This unusual structure allows the membranes of the eardrum to vibrate in response to sound in two distinct ways, with different resonant frequencies. Trying to mimic the Ormia ear in silicon, engineering groups so far have developed prototype "microphone eardrums" that function "Ormia -like" as predicted but at ultrasonic frequencies. Additional research will be needed to generate prototypes that detect sound in the range of normal human hearing, that will be highly directional, fit inside the ear canal, and be affordable. Other applications of the Ormia-inspired silicon ear might include robotic listening devices. These latest findings have led to collaborations between neurobiologists and engineers to make a directional hearing aid that would be smaller, simpler and cost less than currently available devices.

Although hearing aid technology has advance rapidly over the last few decades, the various hearing aids available still do not function well in real world situations where sound from more than one source is present, and they are not particularly effective in restoring the listener's ability to cope with the problem of attending to a single speech source among competing speech sources. NIDCD-supported scientists are actively engaged in research to develop "intelligent" hearing aid systems that are capable of selectively locating and characterizing a sound in a crowd.

Functional Brain Imaging as a Tool to Understand Cochlear Implant Performance. The cochlear implant is the first clinically useful neural sensory prosthesis to replace a human sense. It converts sound into electrical impulses on an array of electrodes that is surgically inserted into the inner ear, bypassing the inner ear hair cells and stimulating the auditory nerve directly, restoring the perception of sound to persons who are totally, or almost totally, deaf. This device has allowed adults who lost their hearing to recover an ability to understand speech. Although speech perception performance of adults has steadily increased with new advances in cochlear implantation, wide performance variations exist among cochlear implant recipients. Differences in structural and functional abnormalities of the auditory system may play a role in this variability. However, little is known about the reorganization of the auditory system following deafness, or on the preservation or recovery of auditory function following cochlear implantation. NIDCD-supported scientists have completed preliminary studies examining functional brain imaging in individuals before and after cochlear implantation. The data suggest that preoperative to postoperative changes in the brain's responsiveness as measured by imaging are related to improvements in speech perception scores. Also, despite relatively similar hearing losses in each ear, significant differences in preoperative auditory cortex activation were observed between ears, which may help guide selection of the more appropriate ear for implantation.

Phase I Clinical Trial of an Otitis Media Vaccine Candidate. Otitis media (OM) is the most common reason for a sick child to be evaluated by a physician, a public health burden estimated to cost approximately $5 billion a year in the U.S. In addition to the cost savings, prevention of OM is particularly important because repeated antibiotic treatment of OM often results in the appearance of drug-resistant strains of bacteria which can no longer be eradicated with first-line antibiotics. NIDCD Intramural scientists have developed candidate vaccines that would protect infants from OM caused by two major bacterial pathogens: nontypeable Haemophilus influenzae and Moraxella catarrhalis. These two pathogens account for two-thirds of OM cases in children, and there is no vaccine available for prevention of the disease. Pre-clinical testing with such vaccines from nontypeable H. influenzae demonstrated that the vaccines could generate specific immunity against the bacteria and reduce bacterial colonization in nose and throat, and reduce the incidence of OM in animal models. Additional clinical trial involving 40 normal human adult volunteers, one such vaccine directed against H. influenzae proved to be both safe and effective, eliciting a significant immune response against the bacteria. This candidate vaccine will soon be tested in a second trial for safety and effectiveness in children. For Moraxella catarrhalis, similar preclinical approaches were taken, resulting in several candidate vaccines. Pre-clinical testing in animal models with vaccines for Moraxella catarrhalis demonstrated that the vaccines were safe and effective, eliciting a significant immune response that inhibited bacterial growth.

Additional clinical trials are planned to test these candidate vaccines for safety and efficacy in humans.

Genetic Testing and the Clinical Management of Nonsyndromic Hereditary Hearing Impairment. In the last decade, approximately 20 genes whose mutations result in nonsyndromic hearing impairment have been identified and isolated. Mutations in one of these genes, GJB2, accounts for about 25% of all autosomal recessive nonsyndromic hereditary hearing impairment in American children. With the identification of genes that contribute to hearing function, genetic testing becomes technically possible but not necessarily suitable for widespread clinical application at present. With the enactment of some type of legislation that requires universal hearing screening for newborns in 36 states, not only are infants with severe hearing impairment identified much earlier in life but infants with lesser degrees of hearing impairment are now also being identified. Many unresolved issues remain for clinicians as they characterize auditory performance in a newborn who fails hearing screening, design intervention strategies to optimize communicative success and ensure that a "medical home" exists for the infant with hearing impairment. The advances in the genetics of hereditary hearing impairment and in the early identification of hearing impairment have now converged. These advances have led some to suggest genetic testing/evaluation for all infants who are identified with a hearing loss at birth. In consideration of these developments, the NIDCD and the National Human Genome Research Institute are collaborating on an initiative to address the clinical relationship between genetic and audiologic/otologic information, as well as to address the clinical validity and utility of genetic testing in the diagnosis, treatment and management of nonsyndromic hereditary hearing impairment.

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