Angiogenic Therapy: Novel Approaches to Enhance Bone Regeneration in Aging - AD/ADRD

血管生成疗法：增强衰老过程中骨再生的新方法 - AD/ADRD

基本信息

批准号：
10711880
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/10711880
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk American Amyloid beta-Protein Animals Apoptotic Biology Blood - brain barrier anatomy Blood Platelets Blood Vessels Bone Regeneration Brain Clinical Research Darkness Data Dementia Development Diagnosis Dose Early Onset Alzheimer Disease Elderly Euthanasia Evans blue stain Female Femoral Fractures Femur Fracture Hip Fractures Histologic Human Impaired cognition Impairment In Vitro Individual Injury Light Link MPL gene Megakaryocytopoieses Mus Mutation Nerve Degeneration Neurons Odds Ratio Oligodendroglia Operative Surgical Procedures Outcome Parents Patients Pharmaceutical Preparations Pharmacotherapy Platelet aggregation Production Property Publishing Race Recording of previous events Risk Risk Factors Roentgen Rays Role SIRT1 gene Senile Plaques Serum Severities Side Signal Pathway Signaling Molecule Sirtuins Symptoms Testing Thrombopoietin Time Transgenic Mice Vascular Dementia aged angiogenesis bone bone fracture repair bone healing cognitive testing dementia risk falls fracture risk frailty high risk improved in vivo inflammatory marker male mouse model neuroinflammation neuropathology neuroprotection novel novel strategies novel therapeutics peptidomimetics prevent sex

项目摘要

SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia in the elderly. 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. The latter findings are associations. To further understand the link between fracture and AD, in this Supplement we will extend our current fracture healing studies as follows. We will complete surgically induced femoral fractures in the 5xFAD mouse model of AD mouse model AD and related dementias (AD/ADRD), where we will examine the progression/severity of AD/ADRD over 12 weeks post-surgery. Because poor angiogenesis is associated with AD/ADRD, we will also determine whether novel fracture healing agents known to improve angiogenesis and fracture healing (thrombopoietic agents or TMPs and sirtuin 1 activator or SRT1720) decrease AD/ADRD progression/severity. Based on these combined ideas, we hypothesize that fracture increases neurodegeneration, neuroinflammation, and the progression/severity of AD/ADRD in the 5xFAD mouse model. We further hypothesize that treatment of fractured mice with SRT1720 or TMP will improve angiogenesis, decrease neurodegeneration, decrease neuroinflammation, and slow/reduce the progression/severity of AD/ADRD. 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 the progression/severity of AD/ADRD. To accomplish this 5xFAD 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 12 weeks post-surgery. Fracture healing, cognitive decline, neurodegeneration, neuroinflammation, vascular biology, and the integrity of the blood brain barrier (BBB) will be assessed. Finally, we will collect brains and serum from mice from the Parent R01 (young [3-4 mo] and old [22-24 mo] mice on a C57BL/6 background without genetic alterations known to impact AD) to assess changes, as detailed above, based on fracture, treatment, and age. Successful completion of this aim will demonstrate whether progression/severity of AD/ADRD is worse following femur fracture. Importantly these studies may demonstrate that treatment of fractures with novel bone healing therapies SRT1720 and/or TMP, which are known to improve angiogenesis and fracture healing, may have the added benefit of attenuating the progression/severity of AD/ADRD.

概括多项研究表明，阿尔茨海默病（AD）是老年人最常见的痴呆症。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。为了进一步了解骨折与 AD 之间的联系，在本补充材料中，我们将扩展我们的研究范围。目前的骨折愈合研究如下。我们将在 5xFAD 中完成手术引起的股骨骨折。 AD 小鼠模型 AD 和相关痴呆症 (AD/ADRD)，我们将在其中检查术后 12 周内 AD/ADRD 的进展/严重程度，因为血管生成不良与此相关。 AD/ADRD，我们还将确定是否有已知的新型骨折愈合剂可以改善血管生成和骨折愈合（血小板生成剂或 TMP 和 Sirtuin 1 激活剂或 SRT1720）减少 AD/ADRD 进展/严重程度。基于这些综合想法，我们认为骨折会增加神经退行性变，我们进一步研究了 5xFAD 小鼠模型中的神经炎症以及 AD/ADRD 的进展/严重程度。坚持认为用 SRT1720 或 TMP 治疗骨折小鼠将改善血管生成，减少神经退行性变，减少神经炎症，并减缓/减少 AD/ADRD 的进展/严重程度。本补充文件提出的目标目标 1. 确定股骨骨折的影响和治疗。使用 SRT1720 或 TMP 治疗股骨骨折对 AD/ADRD 的进展/严重程度的影响。 5xFAD 小鼠将接受基线认知测试，一半小鼠将作为未受伤的对照组，另一半将作为未受伤的对照组。小鼠将接受手术引起的股骨骨折，并接受 SRT1720、TMP 或载体治疗。从手术时开始进行控制，直到手术后 12 周对小鼠进行安乐死，认知能力下降、神经退行性变、神经炎症、血管生物学和血脑完整性最后，我们将从亲本 R01（年轻小鼠）中收集小鼠的大脑和血清。 [3-4 个月] 和老 [22-24 个月] 小鼠，C57BL/6 背景，没有已知影响 AD 的基因改变）如上所述，根据骨折、治疗和年龄评估变化。成功完成这一目标将证明 AD/ADRD 的进展/严重程度是否更糟重要的是，这些研究可能证明用新骨治疗骨折。治疗疗法 SRT1720 和/或 TMP 已知可改善血管生成和骨折愈合，可能具有减轻 AD/ADRD 的进展/严重程度的额外好处。