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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.

总结阿尔茨海默病（AD）是老年人中最常见的痴呆形式。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。后一项调查结果是协会.为了进一步了解骨折和AD之间的联系，在本补充中，我们将扩展我们的目前的骨折愈合研究如下。我们将在5xFAD中完成手术诱导的股骨骨折 AD小鼠模型AD和相关痴呆（AD/ADRD）小鼠模型，其中我们将检查术后12周内AD/ADRD的进展/严重程度。因为不良的血管生成与 AD/ADRD，我们还将确定是否有新的骨折愈合剂已知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SRT 1720）降低AD/ADRD 进展/严重程度。基于这些综合观点，我们假设骨折会增加神经退行性变，神经炎症和AD/ADRD的进展/严重程度。我们进一步假设用SRT 1720或TMP治疗骨折小鼠将改善血管生成，减少因此，本发明的组合物可用于治疗AD/ADRD的神经变性、减少神经炎症和减缓/降低AD/ADRD的进展/严重性。一本补编提出了目标。目标1.确定股骨骨折的影响和治疗使用SRT 1720或TMP治疗股骨骨折对AD/ADRD进展/严重程度的影响。为了实现这一 5xFAD小鼠将进行基线认知测试。一半的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。小鼠将经历手术诱导的股骨骨折。小鼠将接受SRT 1720、TMP或溶剂处理对照从手术时开始，直至手术后12周对小鼠实施安乐死。骨折愈合，认知能力下降、神经变性、神经炎症、血管生物学和血脑的完整性将评估屏障（BBB）。最后，我们将从来自亲本R 01（年轻）的小鼠收集脑和血清 [3-4月龄]和年龄[22-24月龄]的小鼠（C57 BL/6背景，无已知影响AD的遗传改变），如上所述，根据骨折、治疗和年龄评估变化。成功完成该目标将证明AD/ADRD的进展/严重程度是否更差导致股骨骨折重要的是，这些研究可能表明，新骨的骨折治疗已知可改善血管生成和骨折愈合的愈合疗法SRT 1720和/或TMP可具有减轻AD/ADRD的进展/严重程度的额外益处。