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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