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: 8974367
• 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/8974367
• 关键词: Acute; Address; Adult; 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; Elements; Endocytosis; Engineering; Extracellular Matrix; FDA approved; Formulation; Fracture; Genetic study; 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; 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; repaired; response; skeletal; skeletal disorder; wasting

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 目的：骨折具有严重的健康后果，包括冗长的康复和最严重的髋部骨折，可能会导致长时间或永久性残疾，几乎总是需要住院和重大手术。我们已经设计了一种基于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，我们已经确定了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。这些纳米颗粒具有促进新骨形成的潜力，同时减少骨骼崩溃。研究计划：我们的初步研究将自噬的细胞过程确定为潜在的关键机制，我们的纳米颗粒通过该机制差异化成骨细胞和破骨细胞中的细胞功能。自噬是一种高度调节的细胞过程，可以由各种刺激诱导，例如应力，细胞因子，病原体，聚集的蛋白质，受损或多余的细胞器，这些细胞器最终被降解。尽管仅部分理解，但自噬通过靶向蛋白酶体并通过限制IKK/NF-®B途径来限制注射来控制细胞信号传导。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通过刺激成骨细胞和成骨细胞中的自噬来预防和/或逆转与年龄相关的骨质流失的药物。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分化和功能的体外模型来研究我们的纳米颗粒改变功能的机制。我们将研究纳米颗粒诱导的自噬对NF- - B信号传导的影响。我们将利用一种老化诱导的骨质疏松症模型来确定颗粒在促进骨骼体积和钝性骨质流失方面的影响。终点包括对骨骼和血清因子的定量和定性分析，而离体研究将分别解决我们纳米颗粒对体内成骨细胞和破骨细胞的影响。临床相关性：骨折具有严重的健康后果，包括冗长的康复，长期或永久性残疾以及髋部骨折几乎总是需要住院，并相关的重大手术导致发病率增加。相对于裂缝后治疗，预防裂缝将大大减少退伍军人的个人和财务燃烧。可以促进骨质重建的“合成代谢”药物的发展将对田间和骨骼疾病的治疗产生重大影响。目前，没有FDA批准的药物能够实现这一目标以及新型热剂的好处，可以为患有自然发生或疾病相关的骨浪费的患者补充甚至取代当前的疗法。