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

基本信息

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
项目类别：
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&apos 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

项目摘要

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 万人患有缺血性中风，这是导致认知障碍的主要原因。新数据发现中风与其他痴呆症（如阿尔茨海默病）之间存在新的联系大约 25-30% 的缺血性中风幸存者出现立即或延迟的血管认知血小板通过相互作用介导缺血性中风和血管损伤。中性粒细胞会增加炎症，从而导致神经元死亡、认知功能障碍和痴呆。然而，血小板调节缺血性中风的分子机制及其发展血管性痴呆仍然未知。血小板具有动态转录组，并且血小板中的 mRNA 尚不清楚。在血小板中以信号依赖性方式转化为新蛋白质，这是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制靶点 (mTOR)。我们的初步数据表明 mTOR 通路在血小板中发挥作用，并且 mTOR 控制蛋白质合成，包括淀粉样前体蛋白 (APP)，它是此外，我们的数据表明，靶向血小板中的 mTOR 可以改变血小板功能并改善。缺血性中风期间血小板中的 mTOR 是否被激活，以及这对 mRNA 翻译、细胞/代谢功能和结果的影响是前所未有的我们将测试针对血小板中 mTOR 通路的创新假设。改善缺血性中风后的神经和认知结果，从而降低风险我们将采用互补的临床、体外和体内方法，以及最先进的测序技术将严格检验这一假设。确定缺血性中风期间血小板中 mTOR 激活和 mRNA 翻译是否上调。将专门检查 APP 蛋白质合成和 mTOR 控制下的其他蛋白质的调节，导致神经损伤和不良认知结果的具体目标 2 将决定 mTOR 如何进行。血小板的激活调节中风期间的功能反应，包括血小板 mTOR 在中风中的作用调节炎症、脑血流量和血脑屏障破坏，所有这些都有助于具体目标 3 将确定靶向 mTOR 是否可以改善缺血性症状。成功完成这些目标将 1) 确定以下转录本。中风期间血小板的 mTOR 依赖性控制；(2) 确定 mTOR 的破坏是否会减弱血小板 APP 沉积、下游炎症信号传导和血脑屏障通透性；以及 (3) 确定靶向 mTOR 是否可以改善中风后的脑血流量和神经系统结果。生成的数据将显着增加我们对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性痴呆的发展。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Megakaryocyte and Platelet Transcriptomics for Discoveries in Human Health and Disease.

巨核细胞和血小板转录组学在人类健康和疾病中的发现。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Davizon;Rowley, Jesse W;Rondina, Matthew T
通讯作者：
Rondina, Matthew T

The Era of Thromboinflammation: Platelets Are Dynamic Sensors and Effector Cells During Infectious Diseases.

血栓炎症时代：血小板是传染病期间的动态传感器和效应细胞。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Guo, Li;Rondina, Matthew T
通讯作者：
Rondina, Matthew T

Sepsis alters the transcriptional and translational landscape of human and murine platelets.

脓毒症改变了人类和小鼠血小板的转录和翻译景观。

DOI：
发表时间：
2019
期刊：
影响因子：
20.3
作者：
Middleton, Elizabeth A;Rowley, Jesse W;Campbell, Robert A;Grissom, Colin K;Brown, Samuel M;Beesley, Sarah J;Schwertz, Hansjörg;Kosaka, Yasuhiro;Manne, Bhanu K;Krauel, Krystin;Tolley, Neal D;Eustes, Alicia S;Guo, Li;Paine 3rd, Robert;Harris
通讯作者：
Harris

Phospho-inositide-dependent kinase 1 regulates signal dependent translation in megakaryocytes and platelets.

磷酸肌醇依赖性激酶 1 调节巨核细胞和血小板中的信号依赖性翻译。

DOI：
发表时间：
2020-05
期刊：
影响因子：
0
作者：
Manne, Bhanu Kanth;Bhatlekar, Seema;Middleton, Elizabeth A;Weyrich, Andrew S;Borst, Oliver;Rondina, Matthew T
通讯作者：
Rondina, Matthew T

FcγRIIA expression accelerates nephritis and increases platelet activation in systemic lupus erythematosus.

FcγRIIA 表达加速肾炎并增加系统性红斑狼疮中的血小板活化。

DOI：
发表时间：
2020-12-17
期刊：
影响因子：
20.3
作者：
Melki, Imene;Allaeys, Isabelle;Tessandier, Nicolas;Mailhot, Benoit;Cloutier, Nathalie;Campbell, Robert A;Rowley, Jesse W;Salem, David;Zufferey, Anne;Laroche, Audrée;Lévesque, Tania;Patey, Natalie;Rauch, Joyce;Lood, Christian;Droit, Arnaud;M
通讯作者：
M