Angiogenic Therapy: Novel Approaches to Enhance Bone Regeneration in Aging - LOAD

血管生成疗法：增强衰老过程中骨再生的新方法 - LOAD

基本信息

批准号：
10711847
负责人：
Melissa A Kacena
金额：
$ 39.63万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711847
关键词：
Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Animal Model Apoptotic Astrocytes Blood - brain barrier anatomy Blood Platelets Bone Regeneration Central Nervous System Cerebellum Cerebral cortex Clinical Clinical Research Darkness Data Dementia Development Diagnosis Dose Early Onset Alzheimer Disease Economic Burden Elderly Euthanasia Evaluation Evans blue stain Female Femoral Fractures Femur Fracture Funding Heterogeneity Hip Fractures Histologic Human Impaired cognition Individual Injury Late Onset Alzheimer Disease Light Megakaryocytopoieses Mus Neurons Odds Ratio Oligodendroglia Operative Surgical Procedures Outcome Parents Pathology Patients Pharmaceutical Preparations Pharmacotherapy Platelet aggregation Production Race Recording of previous events Risk Risk Factors Roentgen Rays Role SIRT1 gene Side Symptoms TREM2 gene Therapy Evaluation Tight Junctions Time Transgenic Organisms age related aged apolipoprotein E-4 bone fracture repair bone healing clinically relevant cognitive testing cost estimate dementia risk falls field study fracture risk frailty high risk improved in vivo inflammatory marker male model organism mouse model neuroinflammation neuroprotection novel novel strategies novel therapeutics occludin overexpression peptidomimetics prevent protein expression receptor sex therapy development

项目摘要

SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia in the elderly and the vast majority of patients are designated as non-genetically dependent Late-Onset AD (LOAD). Several studies have shown increased risk of fracture with dementia owing in part to increases in falls. On the flip side, several clinical studies have also demonstrated that a fracture history can increase the risk for dementia. Historically, the most widely used mouse models relevant to AD have used transgenic approaches to induce relevant pathologies in young mice. Unfortunately, transgenic overexpression animal models do not effectively produce the heterogeneity observed clinically in LOAD patients and thus are not ideal for therapy development or evaluation. Hence, the NIA-funded Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) Center is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant risk factors. One such mouse model is the aging LOAD mouse (hAbeta/APOE4/Trem2*R47H, Jax #030670). Therefore, as a logical extension of our parent R01 (AG060621), in this AD Supplement, we propose to examine the impact of fracture and our novel fracture therapies on neuroinflammation and the associated cognitive decline in aging LOAD mice. Our parent R01 focuses on developing novel drug therapies such as Sirt1 activator, SRT1720 and thrombopoietic agents to improve fracture healing outcomes in old mice. We found that SRT1720 administered systemically, TPO delivered locally, and TPO mimetic peptides (TMP) delivered systemically were able to improve bone healing. Based on these observations, we hypothesize that fracture increases age-dependent neuroinflammation and cognitive decline in LOAD mice. We further hypothesize that treatment of aging fractured or unfractured LOAD mice with SRT1720 or TMP will reduce neuroinflammation and slow cognitive decline. One Aim is proposed in this Supplement. Aim 1. Determine the effects of a femoral fracture and treatment of femoral fractures with SRT1720 or TMP on neuroinflammation and cognitive decline in aging LOAD mice. To accomplish this aging LOAD mice will undergo baseline cognitive testing. Half of the mice will serve as uninjured controls and half of the mice will undergo a surgically induced femoral fracture. Mice will be treated with SRT1720, TMP, or vehicle control beginning at the time of surgery until mice are euthanized 6 months post- surgery. Fracture healing, cognitive decline, neuroinflammation, the integrity of the Blood Brain Barrier (BBB) will be assessed. Successful completion of this Supplement will determine whether fracture results in more rapid cognitive decline in a novel LOAD mouse model recently developed and characterized by the MODEL-AD consortium. Importantly these studies may demonstrate that treatment with novel bone healing therapies SRT1720 and/or TMP, which are known to improve fracture healing, may have the added benefit of slowing the cognitive decline associated with LOAD.

概括阿尔茨海默氏病（AD）是老年和绝大多数痴呆症的最常见形式患者被指定为非基因依赖性后期AD（负载）。几项研究表明痴呆症的骨折风险增加部分会增加跌倒。另一方面，一些临床研究还证明骨折病史可以增加痴呆症的风险。从历史上看，与AD相关的最广泛使用的鼠标模型使用了转基因方法来诱导年轻小鼠的相关病理。不幸的是，转基因过表达动物模型没有有效在负载患者中产生临床观察到的异质性，因此不是治疗发展的理想选择或评估。因此，NIA资助的模型组织的开发和评估是晚发广告（AD模型）中心正在开发，表征和分发表达人性化的新型小鼠模型，临床相关的风险因素。一个这样的鼠标模型是老化的负载鼠标（HABETA/APOE4/TREM2*R47H， JAX＃030670）。因此，作为我们父母R01（AG060621）的逻辑扩展，在此广告补充中，我们提案，以检查裂缝和我们的新型断裂疗法对神经炎症的影响和老化负荷小鼠的相关认知能力下降。我们的父母R01专注于开发新型药物疗法例如SIRT1激活剂，SRT1720和血小板剂，以改善老鼠的骨折愈合结果。我们发现SRT1720系统地管理，TPO在本地交付，而TPO Mimetic Pepperides（TMP）系统地交付能够改善骨骼的愈合。基于这些观察结果，我们假设断裂增加了依赖年龄的神经炎症负载小鼠的认知能力下降。我们进一步假设对衰老骨折或未分裂的治疗带有SRT1720或TMP的小鼠将减少神经炎症和认知能力下降。一个目的是在此补品中提出。目标1。确定股骨断裂和股骨治疗的影响 SRT1720或TMP的骨折对衰老负荷小鼠的神经炎症和认知能力下降。到完成这种老化的负载小鼠将接受基线认知测试。一半的老鼠将是无伤的对照组和一半的小鼠将发生手术诱导的股骨骨折。老鼠将接受治疗 SRT1720，TMP或车辆控制从手术开始，直到小鼠在6个月后对小鼠安乐死。外科手术。断裂愈合，认知能力下降，神经炎症，血脑屏障的完整性（BBB）将被评估。成功完成此补充剂将确定骨折是否会导致更快的认知能力最近开发和表征的新型负载小鼠模型的下降。重要的是，这些研究可能表明，新型骨骼愈合疗法的治疗SRT1720和/或已知可以改善骨折愈合的TMP可能具有减慢认知能力下降的额外好处与负载相关。