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

描述（由申请人提供）： 目的：骨折有严重的健康后果，包括漫长的康复和最严重的髋部骨折，可能会导致长期或永久性残疾，几乎总是需要住院治疗和大手术。我们设计了一种生物活性二氧化硅纳米颗粒，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，我们已经确定了一个潜在的关键细胞内调节因子的作用，在自噬以及关键的信号通路NF-β B。这些纳米颗粒具有促进新骨形成的潜力，同时减少骨分解。 研究计划：我们的初步研究已经确定自噬的细胞过程是一种潜在的关键机制，通过这种机制，我们的纳米颗粒可以不同地改变成骨细胞和破骨细胞的细胞功能。自噬是一种高度调节的细胞过程，可由各种刺激诱导，如应激、细胞因子、病原体、聚集的蛋白质、最终降解的受损或多余的细胞器。虽然只有部分了解，自噬已被链接到控制细胞信号通过靶向蛋白酶体和限制炎症通过限制IKK/NF-β B途径。基于这些研究，我们假设我们的工程纳米颗粒代表能够通过刺激成骨细胞和破骨细胞中的自噬来预防和/或逆转年龄相关的骨丢失的药剂。 研究方法：为了验证我们的假设，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-β B信号传导的影响。我们将利用老年诱导的骨质疏松症模型来确定我们的颗粒在促进骨体积和钝化骨丢失方面的效果。终点包括骨和血清因子的定量和定性分析，而离体研究将解决我们的纳米颗粒单独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，包括漫长的康复、长期或永久残疾，髋部骨折几乎总是需要住院治疗，并伴有相关的大手术，从而导致发病率增加。预防骨折将大大减轻退伍军人相对于骨折后治疗的个人和经济负担。能够促进丢失的骨量重建的“合成代谢”剂的发展将对该领域和对骨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点，以及补充或甚至取代目前用于患有天然发生的或疾病相关的骨消耗的患者的治疗的新型治疗剂的益处。

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.