Dean A. HaycockSpecial To BioWorld Today

Read this out loud: Your voice creates sound waves that make yourear drums vibrate. The vibrations become pressure waves in the fluidof your inner ear. The fluid sloshes to the changing beat of yourvoice. If your hearing is unimpaired, the sloshing moves sensitivedetectors in your cochlea, called hair cells, back and forth as you readaloud. The hair cells convert the signals in pressure waves intoelectrical impulses. Nerve cells carry the impulses to your brain.

That is how it works if your hearing is unimpaired.

If it is impaired, there is a good chance the problem lies with yourhair cells. Half or more of hearing loss is caused by the death of haircells in the inner ear, according to researchers such as J. CarlOberholtzer, of the department of pathology and laboratory medicine,at the University of Pennsylvania School of Medicine.

In humans and other mammals, hair cells, once destroyed, do notgrow back. The resulting hearing loss is permanent. It is different inbirds. Since 1987, scientists have known that hair cells in subjectswith feathers can regenerate. But how do birds do it? Thebiochemical signals and pathways responsible for the processremained unknown.

Oberholtzer and his colleagues, Dhasakumar Navaratnam, Henry Suand Sean-Patrick Scott have just identified a potentially importantpiece of the molecular machinery that may be responsible in part forhair cell regeneration in chicks. They found that proliferation of haircells is induced by agents that increase levels cyclic AMP (cAMP), asmall ring-shaped molecule that acts as a second messenger invertebrate cells. cAMP is produced when certain hormones ortransmitters interact with specific receptors on cell surfaces. cAMPamplifies messages from outside and carries them into the cell.

The report, "Proliferation in the auditory receptor epitheliummediated by a cyclic AMP-dependent signaling pathway," waspublished today in the October issue of Nature Medicine. In it, theauthors also show that inhibitors of an enzyme regulated by cAMPblocks regeneration of hair cells. Preventing hair cell regeneration byinhibiting the enzyme, cAMP-regulated protein kinase A (PKA),points to a specific intracellular control system involving proteinphosphorylation. Turning on or off protein function by adding andremoving phosphate groups is a common regulatory mechanism incells.

A Surprise, But Not Unprecedented, Finding

People usually do not associate this signaling pathway withstimulating proliferation (of hair cells). "That," Oberholtzerexplained, "is why they are surprised, I suppose. In most tissues andcell types the effects of increasing cAMP levels _ stimulating thiscAMP pathway _ is to stop proliferation and to inducedifferentiation. In many systems proliferation and differentiation areinversely related. However, it is not unprecedented. There aresystems in which cAMP pathways are involved in stimulatingproliferation. One of those is in the thyroid epithelium."

Hair cells can be destroyed by many factors including loud noise,infection, aging and certain types of antibiotics. Oberholtzer's groupshowed that the regeneration of chick hair cells induced in vitro bythe antibiotic gentamicin could be significantly reduced by inhibitorsof cAMP-regulated protein kinase A.

The results are creating a bit of a buzz in the field.

"It is the first instance, I think, of the intracellular pathway beingknown or an element of it identified. There has been some workshowing that growth factors will stimulate proliferation of these cellsbut this [paper] indicates what is going on intracellularly," JeffreyCorwin of the Department of Otolaryngology and Neuroscience at theUniversity of Virginia told BioWorld Today.

The experiments were carried out in chick cochlear tissue which weremaintained in short-term culture. Regeneration of hair cells in thesensory tissue removed from the chicks was detected with DNAsynthesis markers. The identification of this signaling mechanismraises hope of identifying other components of the regenerationprocess.

"It is an area of tremendous opportunity both for scholarship and forbiotechnology companies," Corwin said.

Identifying crucial components of the signaling system responsiblefor regeneration of hair cells could offer biotechnology andpharmaceutical companies multiple therapeutic targets.

"In principle," Oberholtzer said, "one doesn't need to know what theendogenous stimulator is if one has pharmacologic manipulationsdownstream in the pathway."

The fact that hair cells also are crucial components of organs ofbalance in the ear suggests another important potential market fortherapy.

"There is a huge population of individuals who have their quality oflife profoundly affected by hearing loss and by balance disorders thatstem from loss of the sensory cells of the internal ear," Corwin noted."The impact of hearing loss is easy to appreciate but the impact of thebalance disorders that affects many individuals especially in theelderly population should not be underestimated."

There is a good correlation between loss of sensory hair cells and thebalance component of the internal ear. Work by Gary Page at theUniversity of Rochester indicates that this becomes particularlyprofound after age seventy, Corwin said.

Corwin predicted that the first clinical applications of this type ofresearch will be based upon hair cell regeneration therapies for thebalance system rather than hearing.

"It is a simpler sensory epithelium. We have already found that thebasic machinery for a regenerative response occurs in mammals andin human tissue. We don't have as much background information asyet for the hearing part of the system in mammals but the system inmammals does respond in the balance portions of the ear," Corwinsaid.

Next: A Search For Other Kinase Systems

In the meantime, Oberholtzer and his group are planning to look forevidence of the involvement of other kinase systems in theproliferative response.

"It is certainly possible that there are other signaling pathwaysinvolved. We don't yet have evidence that that is the case but itcertainly would not surprise me," Oberholtzer said. The authors areinterested in the possible relationship of the PKA system to othersignaling pathways. One indication that other factors, notsurprisingly, are involved in the regeneration of hair cells arepreliminary results reported by Oberholtzer suggesting that theregeneration does not occur in the absence of serum. Serum is thecomplex and nutrient rich bath that bathes organs in vivo and is usedin tissue culture experiments.

The researchers also want to find out what endogenous factorstimulates the pathway leading to regeneration of hair cells.

"And finally we are very much interested to see if this happens inmammals as well," Oberholtzer said. n

(c) 1997 American Health Consultants. All rights reserved.

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