Cholesterol Homeostasis in Auditory Function

描述(申请人提供)：听力损失是最常见的感官损伤，每1000名新生儿中就有1到6名，近10%的成年人和50%的75岁以上的人受到影响。老年性耳聋是最常见的听力损失原因，涉及与年龄相关的内耳退化，并导致从高频开始的感觉神经性听力损失，并进展到中、低频。虽然动物模型和人类研究支持高胆固醇血症与感觉神经性听力损失之间的联系，这涉及到影响耳蜗、听神经和/或中枢听觉通路的病理，但缺乏基本信息来解释这种关系。机制证据和知识的相对数量，生化状态和种类的耳蜗脂，以及细胞功能如何受到改变的胆固醇动态平衡影响也缺乏。我们假设胆固醇稳态对听力功能和维持是必不可少的，而胆固醇的变化会导致耳蜗和听力功能的下降。我建议确定急性和慢性的全身性胆固醇升高如何影响耳蜗胆固醇的稳态和听力功能，并阐明严重高胆固醇血症影响成人和老年耳蜗病的潜在病理和机制。这些研究将确定血清胆固醇变化、耳蜗内胆固醇动态平衡和听觉功能之间关系的程度和时间性质，并对这种关系背后的病理基础进行理解。随着寿命的延长和普通人口的老龄化，听力损失正成为公共卫生面临的日益严峻的挑战。因此，肥胖和高胆固醇血症患病率的上升要求更好地了解胆固醇稳态是如何影响耳蜗细胞活动和听力功能的。这项提议的结果将成为开发新的治疗方法以保护听觉功能和/或治疗与年龄相关的听力损失的重要基础。

DESCRIPTION (provided by applicant): Hearing loss is the most common sensory impairment, affecting 1 to 6 per 1000 newborns, nearly 10% of the adult population and 50% of those over age 75. Presbycusis is the most common cause of hearing loss, involves age-related degeneration of the inner ear, and results in a sensorineural hearing loss beginning at the high frequencies and progressing to the middle and low frequencies. Although animal models and human studies support a link between hypercholesterolemia and sensorineural hearing loss that implicates pathologies affecting the cochlea, auditory nerve and/or central auditory pathways, fundamental information is lacking to explain this relationship. Mechanistic evidence and knowledge of the relative quantities, biochemical states and species of lipids in the cochlea and how cell functions are affected by altered cholesterol homeostasis are also absent. We hypothesize that cholesterol homeostasis is essential for hearing function and maintenance, and that changes in cholesterol lead to decreased cochlear and hearing function. I propose to determine how acute and chronic elevation of systemic cholesterol affect cochlear cholesterol homeostasis and hearing function and to elucidate the underlying pathologies and mechanisms by which severe hypercholesterolemia affects the adult and aging cochlea. These studies will define the extent and temporal nature of the relationships between alterations in serum cholesterol, cholesterol homeostasis in the cochlea and auditory function, as well as develop an understanding of the pathology underlying this relationship. Hearing loss is becoming an increasing challenge to public health as lifespan increases and the general population ages. As such, the rising prevalence of obesity and hypercholesterolemia demands a better understanding how cholesterol homeostasis influences cochlear cellular activities and hearing function. The outcomes from this proposal will form a crucial basis to develop new therapeutic approaches to preserve auditory function and/or treat age-related hearing loss.