INTERPLAY OF BIOLOGICAL AND PHYSICAL PROCESSES IN OTOCONIAL MORPHOGENESIS

描述（由申请人提供）：耳石是对重力感知和维持平衡至关重要的微观尺寸的生物矿物颗粒。数以百万计的美国老年人的活动能力、生活质量和健康受到耳石进行性脱矿的影响。目前还没有有效的手段来防止或抵制这一进程。在其他系统中，如骨骼和牙齿，主动研究在预防，缓解和修复矿物质缺乏方面取得了惊人的成果。在过去的几年中，许多生物分子参与耳石的形态发生已被确定。我们的目标是阐明所选耳锥基质蛋白的生化和生物物理特性，这些蛋白与矿物相在成核和直接晶体生长的控制中相互作用。生物物理表征依赖于两种互补的技术，即通过传统的生物物理技术以及最近开发的高分辨率质谱技术进行的溶液状态测定。一种不同的方法评估这些基质蛋白质对体外方解石晶体生长的影响，通过SEM和拉曼光谱法进行评估。足够量的基质蛋白的可用性是通过哺乳动物表达系统的重组技术实现这些研究的必要先决条件。重组蛋白生产的依赖是这种方法的根本创新，它将耳锥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置于与更大和更容易进入的矿化结构平等的基础上。希望这个跨学科的团队能成为发展耳锥病研究计划的核心。最终，我们的研究结果应该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“石头”和“沙子”）在维持平衡方面发挥着重要作用。在正常的衰老过程中和许多疾病中，耳石逐渐退化，最终导致失去平衡，福尔斯和骨折。福尔斯是老年人意外死亡的主要原因。我们打算研究的形成，维护和脆弱性耳石使用生物化学和生物物理方法相结合。所获得的信息应最终提供减缓衰老对耳石症的有害影响的方法，其方式类似于我们预防和/或改善龋齿或骨质疏松症的能力。

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.