Platelet Translational Control Mechanisms in Stroke and Vascular Cognitive Dementia

中风和血管性认知痴呆中的血小板翻译控制机制

• 批准号: 10281770
• 负责人: Matthew Thomas Rondina
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10281770
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein Precursor; Attenuated; Blood - brain barrier anatomy; Blood Platelets; Blood Vessels; Brain; Brain Infarction; Brain Ischemia; Cellular Metabolic Process; Cerebrovascular Circulation; Clinical; Cognitive; Data; Dementia; Deposition; Development; Diffusion; FRAP1 gene; Functional disorder; Genes; Genetic Translation; Impaired cognition; In Vitro; Infarction; Inflammation; Inflammatory; Ischemic Stroke; Link; Magnetic Resonance Imaging; Mediating; Messenger RNA; Metabolic; Molecular; Morbidity - disease rate; Motor; Nervous System Physiology; Neurologic; Neurological outcome; Neuronal Injury; Neurons; Neutrophil Infiltration; Outcome; Pathway interactions; Patients; Platelet Activation; Protein Biosynthesis; Proteins; Recording of previous events; Regulation; Risk; Role; Senile Plaques; Signal Transduction; Stroke; Stroke prevention; Techniques; Testing; Time; Transcript; Translating; Translations; Up-Regulation; Vascular Dementia; abeta deposition; beta-site APP cleaving enzyme 1; blood-brain barrier disruption; blood-brain barrier permeabilization; brain tissue; cognitive disability; cognitive function; cognitive testing; experience; functional outcomes; improved; improved outcome; in vivo; innovation; neuroinflammation; neuron loss; neutrophil; novel therapeutics; platelet function; post stroke; public health priorities; response; stroke outcome; stroke survivor; transcriptome; vascular cognitive impairment and dementia; vascular inflammation

About 800,000 people in the U.S. experience ischemic stroke annually, a leading cause of cognitive disability. Emerging data has identified new links between stroke and other dementias, such as Alzheimer’s Disease, with about 25–30% of ischemic stroke survivors developing immediate or delayed vascular cognitive impairment and dementia. Platelets mediate ischemic stroke and vascular damage by interacting with neutrophils to increase inflammation, which leads to neuronal death, cognitive dysfunction, and dementia. However, the molecular mechanism by which platelets regulate ischemic stroke and the development of vascular dementia remain unknown. Platelets possess a dynamic transcriptome and mRNAs in platelets are translated to new proteins in signal-dependent fashion. In platelets, one of the primary pathways controlling mRNA translation and associated cellular and metabolic processes is the mechanistic Target of Rapamycin (mTOR). Our preliminary data demonstrate that the mTOR pathway is functional in platelets, and that mTOR controls protein synthesis, including amyloid precursor protein (APP), a key player in the development of dementia. Moreover, our data suggest that targeting mTOR in platelets alters platelet function and improves ischemic and neurological outcomes in stroke. Whether mTOR is activated in platelets during ischemic stroke, and how this influences mRNA translation, cellular/metabolic functions, and outcomes has never before been rigorously examined. We will test the innovative hypothesis that targeting the mTOR pathway in platelets improves neurological and cognitive outcomes following ischemic stroke, thereby reducing the risk of developing vascular dementia. We will employ complementary clinical, in vitro, and in vivo approaches, along with state-of-the-art sequencing techniques to rigorously test this hypothesis. Specific Aim 1 will determine if mTOR activation and mRNA translation are upregulated in platelets during ischemic stroke. We will specifically examine the regulation of APP protein synthesis and other proteins under mTOR control which contribute to neuronal damage and adverse cognitive outcomes. Specific Aim 2 will determine how mTOR activation in platelets regulates functional responses during stroke, including the role of platelet mTOR in regulating inflammation, cerebral blood flow, and blood brain barrier disruption, all known to contribute to the development of vascular dementia. Specific Aim 3 will establish whether targeting mTOR improves ischemic and neurological outcomes in stroke. Successful completion of these aims will 1) identify transcripts under mTOR-dependent control in platelets during stroke; (2) establish whether disruption of mTOR attenuates platelet APP deposition, downstream inflammatory signaling, and blood brain barrier permeability; and (3) determine whether targeting mTOR improves cerebral blood flow and neurological outcomes following stroke. Data generated will significantly increase our understanding of how translational control pathways in platelets contribute to the pathophysiology of ischemic stroke and the development of vascular dementia.

美国每年约有80万人体验缺血性中风，这是认知障碍的主要原因。 新兴数据已经确定了中风与其他痴呆症之间的新联系，例如阿尔茨海默氏病， 大约25–30％的缺血性中风存活立即发展或延迟血管认知 障碍和痴呆症。血小板培养基缺血性中风和血管损伤通过与 中性粒细胞增加感染，从而导致神经元死亡，认知功能障碍和痴呆。 但是，血小板调节缺血性中风的分子机制和 血管痴呆症仍然未知。血小板具有动态转录组，血小板中的mRNA为 以信号依赖性方式翻译成新蛋白质。在血小板中，控制的主要途径之一 mRNA翻译以及相关的细胞和代谢过程是雷帕霉素的机械靶标 （mtor）。我们的初步数据表明，MTOR途径在血小板中起作用，并且MTOR 控制蛋白质合成，包括淀粉样蛋白前体蛋白（APP），这是开发的关键参与者 失智。此外，我们的数据表明，靶向血小板的MTOR会改变血小板功能并改善 中风的缺血性和神经系统结果。缺血性中风期间是否在血小板中激活mTOR， 以及这如何影响mRNA翻译，细胞/代谢功能和结果 严格检查。我们将测试针对血小板MTOR途径的创新假设 缺血性中风后改善神经系统和认知结果，从而降低了风险 我们将采用完整的临床，体外和体内方法， AIM 1将与最新的测序技术一起进行严格检验该假设。 确定缺血性中风期间血小板中的MTOR激活和mRNA翻译是否更新。我们 将专门检查在MTOR控制下的APP蛋白合成和其他蛋白质的调节， 有助于神经元损害和不良认知结果。特定目标2将决定MTOR 血小板中的激活调节中风过程中的功能反应，包括血小板MTOR在 调节炎症，脑血流量和血脑屏障破坏，所有这些都有助于 血管痴呆的发展。特定目标3将确定靶向mTOR是否改善缺血性 和中风中的神经学结果。这些目标成功完成1）确定成绩单 中风期间血小板中的m依赖性控制； （2）确定MTOR的破坏是否减弱 血小板应用沉积，下游炎症信号传导和血脑屏障渗透性； （3） 确定靶向mTOR是否改善了中风后的脑血流和神经系统结局。 生成的数据将大大增加我们对平移血小板中翻译控制途径的理解 有助于缺血性中风的病理生理学和血管痴呆的发展。

项目成果

Heparanase expression and activity are increased in platelets during clinical sepsis.

• DOI: 10.1111/jth.15266
• 发表时间: 2021-05
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Eustes AS;Campbell RA;Middleton EA;Tolley ND;Manne BK;Montenont E;Rowley JW;Krauel K;Blair A;Guo L;Kosaka Y;Medeiros-de-Moraes IM;Lacerda M;Hottz ED;Neto HCF;Zimmerman GA;Weyrich AS;Petrey A;Rondina MT
• 通讯作者: Rondina MT

Platelet microRNAs inhibit primary tumor growth via broad modulation of tumor cell mRNA expression in ectopic pancreatic cancer in mice.

• DOI: 10.1371/journal.pone.0261633
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wurtzel JGT;Lazar S;Sikder S;Cai KQ;Astsaturov I;Weyrich AS;Rowley JW;Goldfinger LE
• 通讯作者: Goldfinger LE

COVID-19 patients exhibit reduced procoagulant platelet responses.

• DOI: 10.1111/jth.15107
• 发表时间: 2020-11
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Denorme F;Manne BK;Portier I;Petrey AC;Middleton EA;Kile BT;Rondina MT;Campbell RA
• 通讯作者: Campbell RA

Is there a role for the ACE2 receptor in SARS-CoV-2 interactions with platelets?

• DOI: 10.1111/jth.15156
• 发表时间: 2021-01
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Campbell RA;Boilard E;Rondina MT
• 通讯作者: Rondina MT

Identification of genomic loci regulating platelet plasminogen activator inhibitor-1 in mice.

小鼠中调节血小板纤溶酶原激活物抑制剂-1 的基因组位点的鉴定。

• DOI: 10.1016/j.jtha.2023.06.018
• 发表时间: 2023
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Siebert,AmyE;Brake,MarisaA;Verbeek,StephanieC;Johnston,AlexanderJ;Morgan,AndrewP;Cleuren,AudreyC;Jurek,AdriannaM;Schneider,CaitlinD;Germain,DerrikM;Battistuzzi,FabiaU;Zhu,Guojing;Miller,DarlaR;Johnsen,JillM;Pardo-Manu
• 通讯作者: Pardo-Manu