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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.

总结阿尔茨海默氏病（AD）是老年人中最常见的痴呆形式，并且绝大多数老年人患有阿尔茨海默氏病。患者被指定为非遗传依赖性迟发性AD（LOAD）。几项研究表明部分由于福尔斯的增加，老年痴呆症的骨折风险增加。另一方面，一些临床研究也证明了骨折史会增加患痴呆症的风险。历史上，与AD相关的最广泛使用的小鼠模型已经使用转基因方法来诱导年轻小鼠的相关病理学。不幸的是，转基因过表达动物模型不能有效地在LOAD患者中临床观察到异质性，因此对于治疗开发并不理想或评价。因此，NIA资助的迟发性AD模型生物体开发和评估（MODEL-AD）中心正在开发，表征和分发表达人源化，临床相关风险因素。一种这样的小鼠模型是老化LOAD小鼠（hAbeta/APOE 4/Trem 2 * R47 H， Jax #030670）。因此，作为我们的父R 01（AG 060621）的逻辑扩展，在本AD补充中，我们我建议检查骨折和我们的新型骨折疗法对神经炎症的影响，相关认知能力下降。我们的母公司R 01专注于开发新型药物疗法如Sirt 1激活剂、SRT 1720和血小板生成剂，以改善老年小鼠骨折愈合结果。我们发现SRT 1720全身给药，TPO局部给药，TPO模拟肽（TMP）能够改善骨愈合。基于这些观察，我们假设骨折增加了年龄依赖性神经炎症和认知能力下降。我们进一步假设，治疗老化骨折或非骨折，使用SRT 1720或TMP的LOAD小鼠将减少神经炎症并减缓认知能力下降。一个目的是在本附录中提出。目标1.确定股骨骨折和股骨治疗的影响骨折与SRT 1720或TMP对老化LOAD小鼠的神经炎症和认知下降的影响。到完成此老化的LOAD小鼠将经历基线认知测试。一半的老鼠将作为未受伤的对照组和一半的小鼠将经历手术诱导的股骨骨折。小鼠将接受以下处理： SRT 1720、TMP或溶剂对照，从手术时开始，直至小鼠在术后6个月处以安乐死。手术骨折愈合，认知能力下降，神经炎症，血脑屏障（BBB）的完整性将被评估。成功完成本补充将决定骨折是否会导致更快的认知能力最近开发的一种新的LOAD小鼠模型，其特征在于由MODEL-AD联盟。重要的是，这些研究可以证明用新型骨愈合疗法SRT 1720和/或SRT 1722治疗是有效的。 TMP可以促进骨折愈合，可能还有减缓认知能力下降的额外好处与负载有关。