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

• 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
• 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

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.

全脑照射（WBI）导致约50%的长期存活的脑肿瘤患者发生进行性痴呆。 治疗后，至少部分是由于CBF的失调。虽然WBI的具体机制- 虽然目前尚不清楚CBF和认知能力下降是否会引起脑血流减少，但越来越多的证据表明， 神经血管单位起着关键作用。本提案的目的是阐明 辐射诱导的星形胶质细胞功能障碍的认知障碍。核心假设是， 导致星形胶质细胞衰老和随后的功能障碍，改变血管扩张介质的产生 和损害神经血管耦合（NVC）反应。由此产生的神经血管功能障碍有助于 脑血流量下降和认知障碍这项拟议中的工作是新颖的，因为它将是第一个证明 辐射诱导的星形胶质细胞衰老是WBI对大脑影响的关键驱动因素。结果将 可能确定特定的机制，并揭示能够改善脑血流量的潜在疗法。 提供和恢复学习和记忆。提出了以下目标：1）阐明细胞的 WBI诱导的NVC反应受损的潜在机制。工作假设是WBI损害了两者 类花生酸介导的NVC反应和嘌呤能成分。为了在临床上验证这一假设， WBI的相关小鼠模型，将使用激光散斑评估促成NVC反应的途径 对比成像、药理学工具和基于LC/MS/MS的胶质递质释放测量。的 NVC反应药理学上调对WBI处理小鼠认知功能的影响将 测定2)确定辐射诱导的衰老如何改变星形胶质细胞的功能和表型。是 预测辐射诱导星形胶质细胞衰老，这损害了细胞能量代谢， ATP的产生/释放并改变细胞分泌特征，使血管活性物质的合成失调， 脂质介质。为了检验这些假设，将从WBI处理的小鼠中分离衰老星形胶质细胞， 原代人星形胶质细胞培养物将在体外进行辐照。我们将结合联合收割机先进的细胞成像技术 技术和尖端的蛋白质组学和生物化学，以研究细胞能量学，基因表达和 分泌组签名，ATP释放的调节和脂质介质的合成。3)确定 消除衰老细胞是否改善WBI治疗小鼠的NVC和认知功能。据推测 p16依赖性细胞衰老程序的激活是WBI诱导的神经血管 功能障碍和认知障碍。预计衰老细胞的消除，无论是通过遗传 操作（p16- 3 MR小鼠模型）或通过药理学手段将恢复神经血管功能， 改善WBI处理小鼠的认知能力。总之，拟议的研究将确定一个基本机制， 控制与WBI相关的神经血管功能障碍，最终导致认知障碍。

项目成果

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
• 作者: Toth,Peter;Tarantini,Stefano;Rutkai,Ibolya;Ungvari,Zoltan
• 通讯作者: Ungvari,Zoltan

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

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

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-related focal loss of contractile vascular smooth muscle cells in retinal arterioles is accelerated by caveolin-1 deficiency.

• DOI: 10.1016/j.neurobiolaging.2018.06.039
• 发表时间: 2018-11
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Reagan AM;Gu X;Paudel S;Ashpole NM;Zalles M;Sonntag WE;Ungvari Z;Csiszar A;Otalora L;Freeman WM;Stout MB;Elliott MH
• 通讯作者: Elliott MH