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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

基本信息

批准号：
9280823
负责人：
GEORGE R. BECK
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
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/9280823
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 Extracellular Structure FDA approved Formulation Fracture Genetic study Health Hip Fractures Hospitalization In Vitro Individual 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 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

项目摘要

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）：