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：骨折会对健康造成严重后果，包括长期康复，最严重的是髋部骨折，可能会导致长期或永久性残疾，几乎总是需要住院和进行大手术。我们设计了一种能够促进成骨细胞分化和矿化的生物活性二氧化硅纳米颗粒。此外，我们还发现了自噬作用的潜在关键细胞内调节剂以及 NF-¿ B. 这些纳米颗粒有可能促进新骨形成，同时减少骨分解。我们的初步研究已确定自噬的细胞过程是我们的纳米颗粒差异改变成骨细胞和破骨细胞功能的潜在关键机制。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、细胞因子、病原体、聚集的蛋白质、最终被降解的受损或过剩的细胞器。通过靶向蛋白酶体和通过限制 IKK/NF-¿ 来限制炎症，从而与控制细胞信号传导有关基于这些研究，我们发现我们的工程纳米颗粒是一种能够通过刺激成骨细胞和破骨细胞自噬来预防和/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，我们将利用体外技术。成骨细胞和破骨细胞分化和功能模型，以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-¿我们将利用衰老引起的骨质疏松症模型来确定我们的颗粒在促进骨量和减少骨质流失方面的作用，终点包括对骨和血清因素的定量和定性分析，而离体研究将解决 B 信号传导的影响。我们的纳米粒子分别对体内成骨细胞和破骨细胞产生影响：骨折会产生严重的健康后果，包括康复、长期或永久性残疾，并且髋部骨折几乎总是需要住院并进行相关的大手术，从而导致骨折的发病率增加。与骨折后治疗相关的“合成代谢”药物的开发将大大减轻退伍军人的个人和经济负担，这将对该领域和骨疾病的治疗产生重大影响。目前 FDA 批准的任何药物都无法实现这一点，也无法用新型治疗剂来补充甚至替代现有疗法，以治疗患有自然发生的或与疾病相关的骨消耗的患者。