INTERPLAY OF BIOLOGICAL AND PHYSICAL PROCESSES IN OTOCONIAL MORPHOGENESIS

耳圆锥形态发生中生物和物理过程的相互作用

• 批准号: 7532713
• 负责人: RUEDIGER R THALMANN
• 金额: $ 22.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532713
• 关键词: Affect; Aging; Aging-Related Process; American; Benign paroxysmal positional vertigo; Biochemical; Biological; C-terminal; Calcite; Calculi; Cell Nucleus; Cessation of life; Characteristics; Chemistry; Dental caries; Development; Digestion; Discipline; Disease; Elderly; Equilibrium; Force of Gravity; Fracture; Functional disorder; Global Change; Goals; Gravity Perception; Growth; Health; In Vitro; Injury; Labyrinth; Lead; Maintenance; Methods; Microscopic; Minerals; Modality; Modification; Molecular; Morphogenesis; None or Not Applicable; Organ; Osteoporosis; Patients; Peptides; Performance; Phase; Play; Population; Precipitation; Predisposition; Prevention; Process; Production; Property; Prosthesis; Proteins; Purpose; Quality of life; Raman Spectrum Analysis; Rate; Recombinant Proteins; Recombinants; Reliance; Research; Resolution; Role; Science; Silicon Dioxide; Solutions; Standards of Weights and Measures; Structure; System; Techniques; Technology; Testing; Therapeutic; Tooth structure; Work; age effect; aged; alpha-Fetoproteins; analytical ultracentrifugation; biomineralization; biophysical chemistry; bone; demineralization; disorder prevention; falls; foot; improved; innovation; mineralization; multidisciplinary; normal aging; osteopontin; otoconia; otolin-1; particle; physical process; prevent; programs; receptor; repaired; restoration; size; tandem mass spectrometry

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.

描述（由申请人提供）：Otoconia 是一种具有微观尺寸的生物矿物颗粒，对于感知重力和维持平衡至关重要。耳石的逐渐脱矿质影响了数百万美国老年人的行动能力、生活质量和健康。目前还没有有效的方法来阻止或抵消这一过程。在骨骼和牙齿等其他系统中，主动研究在预防、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，已经鉴定出许多参与耳石形态发生的生物分子。我们的目标是阐明选定的耳圆锥基质蛋白在控制成核和直接晶体生长过程中与矿物相相互作用的生化和生物物理特性。生物物理表征依赖于两种互补的技术，即通过传统生物物理技术以及最近开发的高分辨率质谱技术来测定溶液状态。另一种方法通过 SEM 和拉曼光谱法评估这些基质蛋白对体外方解石晶体生长的影响。足够数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。对重组蛋白生产的依赖是该方法的根本创新，它将耳科研究从微观尺寸和难以获得的限制中解放出来。这有效地将耳圆锥研究置于与更大且更容易接近的矿化结构同等的基础上。希望组建的跨学科团队能够成为开发专门的耳圆锥研究项目的核心。最终，我们的研究结果应该会对老年人以及患有耳圆锥功能障碍（例如良性位置性阵发性眩晕（BPPV））的患者的生活质量产生影响。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。在正常的衰老过程和许多疾病中，耳石逐渐退化，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。我们打算结合生物化学和生物物理方法来研究耳石的形成、维持和脆弱性。获得的信息最终应提供减缓衰老对耳石的有害影响的方法，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。