Cholesterol Homeostasis in Auditory Function

描述（由申请人提供）：听力损失是最常见的感觉障碍，每1000名新生儿中有1至6人受到影响，近10%的成年人和50%的75岁以上的人。老年性耳聋是听力损失的最常见原因，涉及与年龄相关的内耳退化，并导致从高频开始并进展到中频和低频的感觉神经性听力损失。虽然动物模型和人类研究支持高胆固醇血症和感觉神经性听力损失之间的联系，涉及影响耳蜗，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。也缺乏关于耳蜗中脂质的相对数量、生化状态和种类以及细胞功能如何受到胆固醇稳态改变影响的机制证据和知识。我们假设胆固醇稳态对听力功能和维持是必不可少的，胆固醇的变化会导致耳蜗和听力功能下降。我建议确定急性和慢性全身胆固醇升高如何影响耳蜗胆固醇稳态和听力功能，并阐明严重高胆固醇血症影响成年和老化耳蜗的潜在病理和机制。这些研究将确定血清胆固醇、耳蜗胆固醇稳态和听觉功能改变之间关系的程度和时间性质，并了解这种关系背后的病理学。随着寿命的延长和普通人群的老龄化，听力损失正在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的患病率不断上升，需要更好地了解胆固醇稳态如何影响耳蜗细胞活动和听力功能。该提案的结果将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奠定重要基础。

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.