Ten million Americans are estimated to have permanent hearing loss from noise exposure and an estimated 30 million more are at risk for hearing loss from daily sound exposure. This proposal investigates how sound causes cochlear vascular pathology and vascular- related loss of cochlear function. Studies of loud sound induced mitochondrial pathophysiology and inflammation will be conducted and emphasize the early mechanisms of sound-induced cochlear damage that are based on nitric oxide (NO), cellular metabolic status and ischemia/reperfusion/inflammatory processes. NO is a major signaling molecule in biological systems. It serves in normal physiology as a vasodilator and a regulator of cellular processes including energy metabolism. It is also involved in tissue pathology through the damage caused by nitrogen related reactive oxygen species (ROS). The proposal has three Aims.
Aim 1 focuses on determining the how loud sound initiates tissue inflammation in the vascular lateral wall of the cochlea. We will first determine the cellular mechanisms of pericytes to control capillary blood flow. Pericytes contact the endothelial cells of the capillaries and receive and produce chemical modulators of blood flow. Sound induced damage has a similarity to ischemia followed by reperfusion (I/R) that occurs in heart infarct and stroke. To investigate tissue inflammation, we study the early events of the Nuclear Factor KappaB (NF-kB) inflammatory pathway. We hypothesize that loud sound causes activation of NF-kB via stimulation of the tumor necrosis factor, a receptor on endothelial cells as in I/R.
Aim 2 determines if the mitochondria of cochlear hair cells (HC) and lateral wall cells are damaged by sound. HCs could have abnormal levels of NO and sodium which may lead to mitochondrial damage. We test whether pharmacological opening of the mitochondrial KATP channel can protect the cells as it does for I/R injury. We believe that future clinical treatments of the early mechanisms of sound damage to hearing function will be useful in reducing the societal impact of the noisy environment.
Aims. Aim 3 investigates whether a certain normal level of NO is necessary for proper function of the inner ear. We study the change of NO induced by loud sound and determine if the change is responsible for the sound induced temporary loss of cochlear sensitivity.
Tens of millions of Americans are estimated to have or be at risk for permanent hearing loss from loud sound exposure. This proposal investigates how sound causes vascular as well as sensory cell damage in the inner ear. The hypothesis is that the sound specifically damages mitochondria in inner ear cells and that it causes inflammation in the in the ear tissues. We believe that a result from this work is that clinical treatments will be found that can reduce sound damage to hearing.
|Wilson, Teresa; Omelchenko, Irina; Foster, Sarah et al. (2014) JAK2/STAT3 inhibition attenuates noise-induced hearing loss. PLoS One 9:e108276|
|Shi, Xiaorui; Zhang, Fei; Urdang, Zachary et al. (2014) Thin and open vessel windows for intra-vital fluorescence imaging of murine cochlear blood flow. Hear Res 313:38-46|
|Floc'h, Johann Le; Tan, Winston; Telang, Ravindra S et al. (2014) Markers of cochlear inflammation using MRI. J Magn Reson Imaging 39:150-61|
|Wu, T; Dai, M; Shi, X R et al. (2011) Functional expression of P2X4 receptor in capillary endothelial cells of the cochlear spiral ligament and its role in regulating the capillary diameter. Am J Physiol Heart Circ Physiol 301:H69-78|
|Dai, Min; Shi, Xiaorui (2011) Fibro-vascular coupling in the control of cochlear blood flow. PLoS One 6:e20652|
|Shi, Xiaorui (2011) Physiopathology of the cochlear microcirculation. Hear Res 282:10-24|
|Ma, Ke-Tao; Guan, Bing-Cai; Yang, Yu-Qin et al. (2011) 2-Aminoethoxydiphenyl borate blocks electrical coupling and inhibits voltage-gated K+ channels in guinea pig arteriole cells. Am J Physiol Heart Circ Physiol 300:H335-46|
|Yang, Yue; Dai, Min; Wilson, Teresa M et al. (2011) Na+/K+-ATPase ?1 identified as an abundant protein in the blood-labyrinth barrier that plays an essential role in the barrier integrity. PLoS One 6:e16547|
|Subhash, Hrebesh M; Davila, Viviana; Sun, Hai et al. (2011) Volumetric in vivo imaging of microvascular perfusion within the intact cochlea in mice using ultra-high sensitive optical microangiography. IEEE Trans Med Imaging 30:224-30|
|Dai, Min; Yang, Yue; Shi, Xiaorui (2011) Lactate dilates cochlear capillaries via type V fibrocyte-vessel coupling signaled by nNOS. Am J Physiol Heart Circ Physiol 301:H1248-54|
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