Radiation-induced astrocyte dysfunction and cognitive decline

辐射引起的星形胶质细胞功能障碍和认知能力下降

基本信息

批准号：
10320428
负责人：
ZOLTAN Istvan UNGVARI
金额：
$ 34.29万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320428
关键词：
Acids Aftercare Astrocytes Biochemistry Brain Brain Injuries Brain Mass Brain Neoplasms Cancer Survivor Cell Aging Cells Cerebrovascular Circulation Cerebrovascular system Cerebrum Cognition Cranial Irradiation DNA DNA Damage Data Dementia Diagnosis Disseminated Malignant Neoplasm Dose Eicosanoids Energy Metabolism Etiology Functional disorder Gene Expression Goals Human Hyperemia Imaging Techniques Impaired cognition Impairment In Vitro Incidence Intervention Laser Speckle Imaging Learning Link Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measurement Mediating Mediator of activation protein Memory Metastatic malignant neoplasm to brain Mitotic Mus Neurologic Symptoms Neurons Newly Diagnosed Outcome Pathogenicity Pathway interactions Patients Persons Pharmacology Phenotype Play Prevention Process Production Prostaglandins Proteomics Publishing Radiation Radiation Tolerance Radiation induced damage Regulation Role Signal Transduction Site Testing Time Up-Regulation Vascular blood supply Vasodilation Vasodilator Agents Work aging brain base brain health cellular imaging cerebral microvasculature clinically relevant cognitive function effective intervention experience genetic manipulation improved irradiation lipid mediator liquid chromatography mass spectrometry malignant breast neoplasm mouse model neurovascular neurovascular coupling neurovascular unit novel prevent programs radioresistant response senescence side effect tool

项目摘要

Whole brain irradiation (WBI) leads to progressive dementia in ~50% of brain tumor patients who survive long- term after treatment, at least in part, due to dysregulation of CBF. Although the specific mechanisms for WBI- induced deceases in CBF and cognitive decline are not yet known, there is increasing evidence that alterations of the neurovascular unit play a crucial role. The objective of this proposal is to elucidate the mechanistic role of irradiation-induced astrocyte dysfunction in cognitive impairment. The central hypothesis is that irradiation causes astrocyte senescence and subsequent dysfunction, altering the production of vasodilator mediators and impairing neurovascular coupling (NVC) responses. The resulting neurovascular dysfunction contributes to decline in CBF and cognitive impairments. The proposed work is novel in that it will be the first to demonstrate that radiation-induced astrocyte senescence is a key driver of the effects of WBI on the brain. The results will likely identify specific mechanisms and reveal potential therapies that are capable of improving cerebral blood supply and restoring learning and memory. The following aims are proposed: 1) Elucidate the cellular mechanisms underlying WBI-induced impairment of NVC responses. The working hypothesis is that WBI impairs both eicosanoid-mediated and purinergic components of NVC responses. To test this hypothesis in a clinically relevant mouse model of WBI, pathways contributing to NVC responses will be assessed using laser speckle contrast imaging, pharmacological tools and LC/MS/MS-based measurement of gliotransmitter release. The impact of pharmacological up-regulation of NVC responses on cognitive function of WBI-treated mice will be determined. 2) Determine how irradiation-induced senescence alters astrocyte function and phenotype. It is predicted that irradiation induces senescence in astrocytes, which impairs cellular energy metabolism and the production/release of ATP and alters the cellular secretory profile, dysregulating the synthesis of vasoactive lipid mediators. To test these hypotheses senescent astrocytes will be isolated from WBI-treated mice and primary human astrocyte cultures will be irradiated in vitro. We will combine advanced cellular imaging techniques and cutting-edge proteomics and biochemistry to investigate cellular energetics, gene expression and secretome signatures, the regulation of ATP release and the synthesis of lipid mediators. 3) Determine whether elimination of senescent cells improves NVC and cognitive function in WBI-treated mice. It is hypothesized that activation of p16-dependent cellular senescence programs is responsible for WBI-induced neurovascular dysfunction and cognitive impairment. It is expected that elimination of senescent cells, either through genetic manipulation (p16-3MR mouse model) or by pharmacological means will restore neurovascular function and improve cognition in WBI-treated mice. Together, the proposed studies will identify a fundamental mechanism governing WBI-related neurovascular dysfunction eventually leading to cognitive impairment.

整个大脑辐照（WBI）导致约50％的脑肿瘤患者的进行性痴呆治疗后的期限至少部分由于CBF的失调。虽然WBI的特定机制尚不清楚CBF诱发的衰落和认知能力下降，越来越多的证据表明改变的变化神经血管单元起着至关重要的作用。该提案的目的是阐明辐照引起的星形胶质细胞功能障碍在认知障碍中。中心假设是辐照导致星形胶质细胞衰老和随后的功能障碍，改变血管扩张剂介质的产生并损害神经血管耦合（NVC）反应。由此产生的神经血管功能障碍有助于 CBF和认知障碍的下降。拟议的工作是新颖的，因为它将是第一个证明辐射引起的星形胶质细胞衰老是WBI对大脑作用的关键驱动力。结果将可能识别特定机制并揭示能够改善脑血液的潜在疗法供应和恢复学习和记忆。提出了以下目的：1）阐明细胞 WBI诱导的NVC响应损害的机制。工作的假设是WBI都会损害 NVC响应的eicosanoid介导的和嘌呤能成分。在临床上检验该假设 WBI的相关鼠标模型，将使用激光斑点评估有助于NVC响应的途径对比成像，药理学工具和基于LC/MS/MS/MS/MS/MS/MS的测量。这 NVC反应的药理上调对WBI治疗小鼠认知功能的影响将是决定。 2）确定辐射诱导的衰老如何改变星形胶质细胞功能和表型。这是预测辐射会诱导星形胶质细胞衰老，这会损害细胞能量代谢和 ATP的生产/释放并改变细胞分泌概况，使血管活性的合成失调脂质介体。为了检验这些假设，衰老的星形胶质细胞将从WBI处理的小鼠中分离出来，原发性人星形胶质细胞培养物将在体外得到照射。我们将结合先进的蜂窝成像技术和尖端蛋白质组学和生物化学，以研究细胞能量学，基因表达和分泌的特征，ATP释放的调节和脂质介质的合成。 3）确定消除衰老细胞是否可以改善WBI治疗小鼠的NVC和认知功能。它是假设的 p16依赖性细胞衰老程序的激活负责WBI诱导的神经血管功能障碍和认知障碍。预计消除衰老细胞是通过遗传操纵（P16-3MR小鼠模型）或通过药理学手段将恢复神经血管功能和改善WBI治疗小鼠的认知。拟议的研究将共同确定基本机制管理与WBI相关的神经血管功能障碍最终导致认知障碍。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Assessment of endothelial function in leptomeningeal arterioles derived from patients with Alzheimer's disease and vascular cognitive impairment.

评估阿尔茨海默病和血管性认知障碍患者的软脑膜小动脉的内皮功能。

DOI：
10.1152/ajpheart.00367.2018
发表时间：
2018
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Toth,Peter;Tarantini,Stefano;Rutkai,Ibolya;Ungvari,Zoltan
通讯作者：
Ungvari,Zoltan

Myocardial ischemia: lack of coronary blood flow, myocardial oxygen supply-demand imbalance, or what?

DOI：
10.1152/ajpheart.00139.2019
发表时间：
2019-06-01
期刊：
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
影响因子：
4.8
作者：
Heusch, Gerd
通讯作者：
Heusch, Gerd

Vascular mechanisms leading to progression of mild cognitive impairment to dementia after COVID-19: Protocol and methodology of a prospective longitudinal observational study.

DOI：
10.1371/journal.pone.0289508
发表时间：
2023
期刊：
PloS one
影响因子：
3.7
作者：
通讯作者：

Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice.

药理诱导的神经血管耦合反应损伤会改变小鼠的步态协调性。

DOI：
10.1007/s11357-017-0003-x
发表时间：
2017
期刊：
GeroScience
影响因子：
5.6
作者：
Tarantini,Stefano;Yabluchanksiy,Andriy;Fülöp,GáborA;Hertelendy,Peter;Valcarcel-Ares,MNoa;Kiss,Tamas;Bagwell,JonathanM;O'Connor,Daniel;Farkas,Eszter;Sorond,Farzaneh;Csiszar,Anna;Ungvari,Zoltan
通讯作者：
Ungvari,Zoltan

Age-dependent cardiovascular effects of sepsis in a murine model of cecal ligation and puncture: implications for the design of interventional studies.

盲肠结扎和穿刺小鼠模型中败血症的年龄依赖性心血管影响：对干预研究设计的影响。