IMPACT OF ASTROCYTE MITOCHONDRIAL METABOLISM ON NEUROPROTECTION DURNING AGING

星形胶质细胞线粒体代谢对衰老过程中神经保护的影响

基本信息

批准号：
7233108
负责人：
JAMES D LECHLEITER
金额：
$ 18.14万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7233108
关键词：
Affect Aftercare Age Aging Aging-Related Process Ally Animal Model Animals Antioxidants Apoptosis Apoptotic Applications Grants Appointment Area Astrocytes Autophagocytosis Award Basic Science Beds Biochemical Reaction Biological Markers Biological Models Biomedical Research Bone Resorption Brain Brain imaging Calcium/calmodulin-dependent protein kinase Calmodulin Cancer Center Support Grant Cardiovascular Diseases Caspase Cause of Death Cells Cessation of life Chemicals Clinical Research Collaborations Complex Computer software Condition Critiques Cultured Cells Cyclotrons Data Dental Schools Dependence Development Diabetes Mellitus Dietary Intervention Diquat Disease Doctor of Medicine Doctor of Philosophy Down-Regulation Education Educational Activities Elderly Electronics Endopeptidases Energy Metabolism Enrollment Ensure Environment Equipment Event Excision Faculty Fluorescence Fostering Foundations Frequencies Funding Generations Genes Geriatrics Goals Grant Group Meetings Guidelines Head Health Health Sciences Healthcare Hepatocyte Hispanics Hospitals Hour Housing Human Resources Image Imaging technology In Vitro Incubators Individual Induction of Apoptosis Institutes Institution Knockout Mice Knowledge Laboratories Left Life Light Link Liquid substance Liver Longevity LysoTracker Malignant Neoplasms Manuscripts Measurement Measures Mediating Mediator of activation protein Medical Medical center Membrane Potentials Metabolism Mexican Americans Microscopic Mitochondria Mitochondrial DNA Modeling Molecular Molecular Biology Molecular Genetics Multiple Myeloma Mus Muscle NADP Nature Neurons Nitrogen Numbers Nursing Schools Optics Organ Organism Organization administrative structures Osteoblasts Osteoclasts Osteogenesis Osteoporosis Other Finding Oxidants Oxidative Stress Participant Pathology Pathway interactions Peptide Hydrolases Phenotype Phosphotransferases Physiological Physiology Play Poison Positron Postdoctoral Fellow Preparation Principal Investigator Process Production Program Research Project Grants Progress Reports Protein Chemistry Protein Overexpression Proteins Publications Publishing Purinoceptor Purpose Qualifying Quality Control Radiochemistry Radioisotopes Radiolabeled Radiology Specialty Range Rate Recruitment Activity Research Research Infrastructure Research Personnel Research Project Grants Research Support Resources Review Literature Role Schedule School Nursing Schools Science Seasons Skeleton Slice South Texas Staining method Stains Stress Students System Techniques Testing Texas Therapeutic Time Tissues Transgenic Mice Transgenic Organisms Universities Urine Veterans Hospitals Week Wild Type Mouse Work abstracting age related aging nutrition animal facility astrocyte mediated neuroprotection base biological adaptation to stress bone bone loss caspase-2 cell injury concept design experience improved in vitro Assay in vivo in vivo Model insight juvenile animal luminescence malignant breast neoplasm medical schools member mitochondrial dysfunction mitochondrial membrane multidisciplinary neuroprotection normal aging novel oxidation prevent pro-caspase-2 programs protein purification radiotracer repaired research study respiratory response single photon emission computed tomography structural biology tissue culture tumor

项目摘要

Bone is a living organ that is maintained through continuous formation of new bone by osteoblasts and resorption of exiting bone by osteoclasts. Loss of bone mass at advanced ages causes osteoporosis. Caspase-2 is a protease that is involved in programmed cell death (apoptosis). During the last funding period, we found that caspase-2 is an important regulator of bone mass in aging animals. Our critical observation was that aging-associated bone loss in old (24-26 month) caspase-2 null mice was more severe than that in the same age wild type mice. The objective of this proposal is to further study the role of caspase-2 in aging skeleton. Our hypothesis is that caspase-2 mediates mitochondrial-dependent apoptosis of aging osteoclasts, which is induced by oxidative stress in vivo. Lack of caspase-2 activity results in reduced apoptosis of aging osteoclasts, leading to increased bone resorption. To test this hypothesis, first, we will compare the rate of bone formation and bone resorption in old caspase-2 null and wild type mice to show that caspase-2 affects bone resorption. Next, we will compare the apoptosis rate in aging osteoclasts that have increased/decreased antioxidant capacity to show that oxidative stress is a cause of spontaneous apoptosis of aging osteoclasts. Then, we will compare the apoptosis rate of caspase-2 (-/-)and (+/+) aging osteoclasts to show that caspase-2 plays an important role in the spontaneous apoptosis of aging osteoclasts. Finally, we will compare the apoptosis rate in aging osteoclasts that have both altered antioxidant activity and caspase-2 activity to show that caspase-2 is a mediator of oxidative stress-induced apoptosis. Calmodulin (CaM) dependent kinase II (CaMK II) can phosphorylate procaspase-2 and prevent its activation. NADPH, which provides reducing equivalent for various biochemical reactions to scavenge oxidants, also inhibits the activation of procaspase-2 by enhancing CaMK II function. Based on these findings, we will test the hypothesis that oxidative stress activates caspase-2 in aging osteoclasts through down-regulation of NADPH/CaMK II activity by examining the level of NAPDH and oxidation of CaM and CaMK II. Osteoporosis is a serious disease that affects the elderly. The main strategy and mechanism of action of current anti-osteoporosis therapy is to induce osteoclast apoptosis. Therefore, this study will shed the light on the mechanism of apoptosis in osteoclasts and open new avenues for new anti-osteoporosis therapies.

骨骼是一个活的器官，通过成骨细胞和成骨细胞不断形成新骨来维持破骨细胞对现有骨的吸收。年老时骨质流失会导致骨质疏松症。 Caspase-2 是一种参与程序性细胞死亡（细胞凋亡）的蛋白酶。上次融资期间期间，我们发现caspase-2是衰老动物骨量的重要调节因子。我们的批评观察发现，老年（24-26 个月）caspase-2 缺失小鼠中与衰老相关的骨质流失更为严重与同龄野生型小鼠相比。本提案的目的是进一步研究衰老骨骼中的 caspase-2。我们的假设是 caspase-2 介导线粒体依赖性细胞凋亡破骨细胞老化，这是由体内氧化应激引起的。 caspase-2 活性缺乏会导致减少老化破骨细胞的凋亡，导致骨吸收增加。为了检验这个假设，首先，我们将比较老年 caspase-2 无效小鼠和野生型小鼠的骨形成和骨吸收率表明 caspase-2 影响骨吸收。接下来我们比较一下衰老破骨细胞的凋亡率抗氧化能力增加/减少，表明氧化应激是自发性老化破骨细胞的凋亡。然后，我们将比较caspase-2 (-/-)和(+/+)老化的凋亡率破骨细胞表明caspase-2在衰老自发凋亡中发挥重要作用破骨细胞。最后，我们将比较老化破骨细胞的凋亡率，这些破骨细胞都发生了改变抗氧化活性和 caspase-2 活性表明 caspase-2 是氧化应激诱导的介质细胞凋亡。钙调蛋白 (CaM) 依赖性激酶 II (CaMK II) 可以磷酸化 procaspase-2 并预防它的激活。 NADPH，为各种生化反应提供还原当量以清除氧化剂，还通过增强 CaMK II 功能来抑制 procaspase-2 的激活。基于这些研究结果，我们将测试氧化应激通过以下方式激活老化破骨细胞中的 caspase-2 的假设：通过检查 NAPDH 水平和 CaM 氧化来下调 NADPH/CaMK II 活性钙MK II。骨质疏松症是一种影响老年人的严重疾病。主要策略和机制目前抗骨质疏松治疗的作用是诱导破骨细胞凋亡。因此，本研究将揭示揭示破骨细胞凋亡机制，为新的抗骨质疏松症开辟新途径疗法。