INTERPLAY OF BIOLOGICAL AND PHYSICAL PROCESSES IN OTOCONIAL MORPHOGENESIS

描述（由申请人提供）：耳石是微小大小的生物矿物颗粒，对感知重力和维持平衡至关重要。数以百万计的美国老年人在他们的行动能力，生活质量和健康受到影响的进行性耳蜗脱矿。目前没有有效的手段来防止或抵消这一过程。在骨骼和牙齿等其他系统中，主动研究在预防、减轻和修复矿物质缺乏方面取得了显著成果。在过去的几年里，许多参与耳蜗形态发生的生物分子已经被发现。我们的目的是阐明选定的耳锥基质蛋白的生化和生物物理特性，这些蛋白与矿物相相互作用，控制着成核和直接晶体生长。生物物理表征依赖于两种互补的技术，即利用传统生物物理技术测定溶液状态以及最近发展起来的高分辨率质谱技术。另一种不同的方法评估这些基质蛋白对方解石晶体生长的影响，通过扫描电镜和拉曼光谱进行评估。获得足够数量的基质蛋白是通过重组技术通过哺乳动物表达系统实现这些研究的必要前提。依靠重组蛋白的生产是这种方法的根本创新，它将耳锥体研究从微观尺寸和难以接近的限制中解放出来。这有效地将耳锥研究与更大、更容易接近的矿化结构置于同等地位。希望集结的跨学科团队将成为一个专门的耳科研究项目发展的核心。最终，我们的研究结果将对老年人的生活质量产生影响，以及特别患有耳锥功能障碍的患者，如良性位置性阵发性眩晕（BPPV）。耳石和耳石（分别来自拉丁语的“石头”和“沙子”）在维持平衡方面起着至关重要的作用。在正常的衰老过程和许多疾病中，耳蜗逐渐退化，最终导致失去平衡、跌倒和骨折。跌倒是老年人意外死亡的主要原因。我们打算用生物化学和生物物理相结合的方法来研究耳郭的形成、维持和脆弱性。获得的信息应该最终提供减缓衰老对耳聋的有害影响的方法，就像我们预防和/或改善龋齿或骨质疏松症的能力一样。

DESCRIPTION (provided by applicant): Otoconia are biomineral particles of microscopic size essential for perception of gravity and maintenance of balance. Millions of older Americans are affected in their mobility, quality of life, and health by a progressive demineralization of otoconia. Currently no effective means to prevent or counteract this process are available. In other systems, such as bone and teeth, initiative research has yielded spectacular results in prevention, alleviation and repair of mineral deficiencies. In the past few years numerous biomolecules involved in the morphogenesis of otoconia have been identified. Our objective is to elucidate the biochemical and biophysical properties of selected otoconial matrix proteins underlying interaction with the mineral phase in the control of nucleation and direct crystal growth. Biophysical characterization relies on two complementary techniques, solution state determination by means of traditional biophysical techniques as well as the recently developed High Resolution Mass Spectrometric techniques. A different approach assesses the influence of these matrix proteins upon calcite crystal growth in vitro, evaluated by SEM and Raman Spectrometry. Availability of sufficient quantities of matrix proteins is an essential prerequisite for these studies to be achieved by recombinant techniques by means of mammalian expression systems. Reliance upon recombinant protein production is the fundamental innovation of this approach, which liberates otoconial research from the constraints of microscopic size and difficult accessibility. This effectively places otoconial research on equal footing with much larger and readily accessible mineralized structures. It is hoped that the assembled interdisciplinary team will serve as nucleus for the development of a dedicated otoconial research program. Ultimately our findings should have impact on the quality of life of the aged, as well as patients specifically afflicted with otoconial dysfunctions, such as benign positional paroxysmal vertigo (BPPV). Otoliths and otoconia (from Latin 'stones' and 'sand', respectively) play an essential role in the maintenance of balance. In the normal aging process and in numerous diseases otoconia gradually degenerate, eventually resulting in loss of balance, falls and bone fracture. Falls are the leading cause of accidental death in the elderly population. We intend to study the formation, maintenance and vulnerability of otoconia using a combination of biochemical and biophysical approaches. Information gained should ultimately provide means to slow down the deleterious effects of aging on otoconia, in a manner similar to our ability to prevent and/or ameliorate dental caries or osteoporosis.