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.

概括阿尔茨海默病 (AD) 是老年人中最常见的痴呆症，绝大多数人多项研究表明，患者被指定为非遗传依赖性迟发性 AD (LOAD)。另一方面，多项临床研究表明，骨折合并痴呆的风险增加，部分原因是跌倒次数增加。还证明，骨折史会增加患痴呆症的风险。历史上，最广泛使用的与 AD 相关的小鼠模型都使用转基因方法来诱导不幸的是，转基因过度表达动物模型并不能有效地治疗幼鼠的相关病理。产生临床上在 LOAD 患者中观察到的异质性，因此对于治疗开发来说并不理想因此，NIA 资助了迟发性 AD 的模型生物体开发和评估。 (MODEL-AD) 中心正在开发、表征和分发表达人性化、一种此类小鼠模型是衰老 LOAD 小鼠 (hAbeta/APOE4/Trem2*R47H， Jax #030670）因此，作为我们的父 R01 (AG060621) 的逻辑扩展，在本 AD 补充中，我们提议检查骨折和我们的新型骨折疗法对神经炎症和神经炎症的影响与衰老 LOAD 小鼠相关的认知能力下降我们的母体 R01 专注于开发新的药物疗法。例如 Sirt1 激活剂、SRT1720 和血小板生成剂，可改善老年小鼠的骨折愈合结果。我们发现 SRT1720 全身给药，TPO 局部递送，TPO 模拟肽 (TMP) 全身给药能够改善骨愈合。根据这些观察，我们发现骨折会增加年龄依赖性神经炎症我们进一步研究了老年骨折或未骨折的治疗方法。使用 SRT1720 或 TMP 的 LOAD 小鼠将减少神经炎症并减缓认知能力下降。本补充文件中提出的目标 1. 确定股骨骨折和股骨治疗的影响。 SRT1720 或 TMP 治疗骨折对衰老 LOAD 小鼠神经炎症和认知能力下降的影响。完成这一目标的老化 LOAD 小鼠将接受基线认知测试，其中一半的小鼠将保持未受伤状态。对照组和一半的小鼠将接受手术引起的股骨骨折。 SRT1720、TMP 或载体对照从手术时开始，直至小鼠在术后 6 个月被安乐死骨折愈合、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 MODEL-AD 联盟最近开发并表征的新型 LOAD 小鼠模型的下降。重要的是，这些研究可能证明新型骨愈合疗法 SRT1720 和/或 TMP 已知可以改善骨折愈合，可能还有减缓认知能力下降的额外好处与负载相关。