Bio-active Nanoparticles and the stimulation of autophagy for improved bone mass

生物活性纳米颗粒和刺激自噬以改善骨量

• 批准号: 8634211
• 负责人: GEORGE R. BECK
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634211
• 关键词: Acute; Address; Adult; Age; Age-Related Bone Loss; Aging; Anabolic Agents; Artificial nanoparticles; Autophagocytosis; Autophagosome; Binding; Biological; Biomechanics; Bone Density; Bone Diseases; Cell Culture Techniques; Cell physiology; Cells; Development; Devices; Disease; Drug Formulations; Elements; Endocytosis; Engineering; Extracellular Matrix; FDA approved; Fracture; Genetic; Health; Hip Fractures; Hospitalization; In Vitro; Inflammation; Knockout Mice; Link; Lysosomes; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; NF-kappa B; Nanotechnology; Operative Surgical Procedures; Organelles; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Phenotype; Phosphotransferases; Prevention; Property; Proteins; Publishing; Rehabilitation therapy; Relative (related person); Research; Role; Serum; Signal Pathway; Signal Transduction; Silicon Dioxide; Stimulus; Stress; Structure; Testing; Therapeutic Agents; Therapeutic Uses; Tissues; Veterans; age related; aged; base; biomaterial compatibility; bone; bone loss; bone mass; bone metabolism; bone turnover; clinically relevant; cytokine; disability; improved; in vitro Model; in vivo; mineralization; mouse model; multicatalytic endopeptidase complex; multidisciplinary; nanomaterials; nanoparticle; nanoscale; new therapeutic target; novel; novel therapeutics; osteoblast differentiation; osteoclastogenesis; particle; pathogen; prevent; protein aggregate; protein degradation; public health relevance; repaired; response; skeletal; skeletal disorder; wasting

Objectives: Fractures have serious health consequences including lengthy rehabilitation and the most serious, hip fractures, may cause prolonged or permanent disability and almost always require hospitalization and major surgery. We have engineered a bio-active silica based nanoparticle capable of promoting osteoblast differentiation and mineralization while inhibiting osteoclastogenesis. Furthermore, we have identified a potential key intracellular regulator of the effect in autophagy as well as key signaling pathway in NF-¿B. These nanoparticles have the potential to promote new bone formation while simultaneously reducing bone breakdown. Research Plan: Our preliminary studies have identified the cellular process of autophagy as a potential key mechanism by which our nanoparticles differentially alter cell function in osteoblasts and osteoclasts. Autophagy is a highly regulated cellular process that can be induced by various stimuli, such as stress, cytokines, pathogens, aggregated proteins, damaged or surplus organelles that are ultimately degraded. Although only partially understood, autophagy has been linked to controlling cell signaling by targeting the proteasome and restricting inflammation through limiting the IKK/NF-¿B pathway. Based on these studies we hypothesize that our engineered nanoparticle represents an agent capable of preventing and/or reversing age- related bone loss by stimulating autophagy in osteoblasts and osteoclasts. Methods: To test our hypothesis we will utilize we will utilize in vitro models of osteoblast and osteoclast differentiation and function to investigate the mechanism(s) by which our nanoparticles alter function. We will investigate the effects of nanoparticle induced autophagy on NF-¿B signaling. We will utilize a model of aged induced osteoporosis to determine the effect of our particles in both promoting bone volume and blunting bone loss. Endpoints include a quantitative and qualitative analysis of bone and serum factors while ex vivo studies will address the effects of our nanoparticles individually on osteoblasts and osteoclast in vivo. Clinical Relevance: Fractures have serious health consequences including lengthy rehabilitation, prolonged or permanent disability, and hip fractures almost always require hospitalization with associated major surgery leading to increased morbidity. Prevention of fractures will greatly reduce both the personal and financial burden to veterans relative to post-fracture treatment. The development of "anabolic" agents that can promote the rebuilding of lost bone mass would represent a significant impact on the field and on the treatment of bone disease. No current FDA approved agent is able to achieve this and the benefits of a novel therapeutic agent to supplement, or even replace, current therapies for patients suffering from either naturally occurring or disease associated bone wasting.

目标：骨折会造成严重的健康后果，包括长期康复和最严重的损伤。 严重的髋部骨折，可能导致长期或永久性残疾，几乎总是需要住院治疗 和大手术。我们设计了一种具有生物活性的二氧化硅纳米颗粒，能够促进成骨细胞 分化和矿化，同时抑制破骨细胞生成。此外，我们还确定了一个 自噬作用的潜在关键细胞内调节剂以及 NF-¿B 中的关键信号通路。这些 纳米粒子有可能促进新骨形成，同时减少骨量 分解。 研究计划：我们的初步研究已确定自噬的细胞过程是一个潜在的关键 我们的纳米颗粒差异改变成骨细胞和破骨细胞的细胞功能的机制。 自噬是一种高度调控的细胞过程，可以由各种刺激诱导，例如压力、 最终被降解的细胞因子、病原体、聚集的蛋白质、受损或过剩的细胞器。 尽管只有部分了解，但自噬已通过靶向 蛋白酶体并通过限制 IKK/NF-¿B 通路来限制炎症。基于这些研究我们 假设我们的工程纳米颗粒代表了一种能够预防和/或逆转年龄的药物 通过刺激成骨细胞和破骨细胞的自噬来减少相关的骨质流失。 方法：为了检验我们的假设，我们将利用成骨细胞和破骨细胞的体外模型 分化和功能来研究我们的纳米粒子改变功能的机制。我们将 研究纳米粒子诱导的自噬对 NF-¿B 信号传导的影响。我们将利用老年模型 诱导骨质疏松症，以确定我们的颗粒在促进骨体积和钝化骨方面的作用 损失。终点包括体外研究时对骨和血清因素的定量和定性分析 将解决我们的纳米颗粒对体内成骨细胞和破骨细胞的影响。 临床相关性：骨折会造成严重的健康后果，包括长期康复、长期 或永久性残疾，髋部骨折几乎总是需要住院并进行相关的大手术 导致发病率增加。预防骨折将大大减少个人和经济损失 退伍军人骨折后治疗的负担。开发可以促进的“合成代谢”药物 重建丢失的骨量将对骨领域和治疗产生重大影响 疾病。目前 FDA 批准的任何药物都无法实现这一目标以及新型治疗剂的益处 补充，甚至取代目前针对自然发生或患有疾病的患者的治疗方法 与骨消耗相关的疾病。