Vermont Center for Cardiovascular and Brain Health

佛蒙特州心血管和脑健康中心

• 批准号: 10854365
• 负责人: MARY CUSHMAN
• 金额: $ 66.05万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-06 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10854365
• 关键词: Administrative Supplement; Affect; Award; Biological; Blood Vessels; Blood capillaries; Blood flow; Capillary Endothelial Cell; Cardiovascular Diseases; Cations; Cell membrane; Central Nervous System; Cerebrovascular Circulation; Cholesterol; Collaborations; Cues; Data; Development; Disease; Electrophysiology (science); Endothelial Cells; Endothelium; Engineering; Environment; Erythrocytes; Event; Fostering; Foundations; Friction; Funding; Future; Health; Hyperemia; Image; Impaired cognition; Ion Channel; Lipid Bilayers; Lipids; Location; Measures; Mechanical Stimulation; Mediating; Membrane; Membrane Fluidity; Membrane Lipids; Membrane Potentials; Metabolic; Mutation; National Institute of General Medical Sciences; Neurons; Parents; Phase; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Piezo 1 ion channel; Positioning Attribute; Potassium Channel; Preparation; Process; Productivity; Proteins; Regional Blood Flow; Research; Resolution; Retina; Role; Science; Scientist; Signal Transduction; Societies; Solid; Stroke; System; Techniques; Testing; Time; Transgenic Mice; Translating; Travel; United States National Institutes of Health; Vermont; Work; arteriole; brain health; brain tissue; cardiovascular health; career; cerebral capillary; early-career faculty; feeding; fluidity; force sensor; gain of function; interest; mechanical force; mechanical stimulus; mouse model; neural; neurotransmission; neurovascular coupling; novel; patch clamp; pharmacologic; programs; recruit; regenerative; response; sensor; shear stress; superresolution microscopy

Project Summary: Cerebral blood flow is precisely controlled to satisfy neuronal metabolic demands. Active neurons signal to the vasculature via multiple neurovascular coupling mechanisms to increase regional blood flow in a phenomenon known as functional hyperemia. The hyperemic response increases the frictional forces imposed by blood flow onto endothelial cells of arterioles and capillaries. We have recently demonstrated that the Piezo1 channel is a crucial mechanosensor in brain capillary endothelial cells, and that it mediates Ca2+ signals in response to mechanical stimuli. Previous research has focused on mechanisms engaged downstream of endothelial Piezo1 activation, but how endothelial cell plasma membrane fluidity controls its activity remains unknown. In response to the NIH Notice of Special Interest (NOT-GM-23-034) “Availability of Administrative Supplements to IDeA Awards to Fund Team Science Development Projects,” we provide compelling preliminary evidence that lipid domains enriched in cholesterol and phosphoinositides exist in central nervous system capillary networks. Further, we propose and provide preliminary results that lipids affect Piezo1 activity. The parent award, supported by NIGMS (P20GM135007), provides a platform to build sustainable research programs built on the exceptional potential of early career faculty to study the vital health problems facing society: cardiovascular disease, stroke and cognitive impairment. This Team Science proposal aims to lay the foundation and framework for Drs. Harraz (current Project Director, P20GM135007) and Gonzales (former Project Director, P20GM130459) to build upon their past productive collaborations and bring their expertise and techniques to synergistic work on impactful biological questions. Herein, we hypothesize that the lipids cholesterol and phosphatidylinositol-4,5- bisphosphate (PIP2) form domains in capillary networks, which determine capillary endothelial membrane fluidity and Piezo1 activity. To test this hypothesis, the proposed Team Science project will use diverse, state-of-the-art approaches, including patch-clamp electrophysiological techniques and engineered mouse models (Harraz Lab) along with high-resolution vascular imaging (Gonzales Lab) to characterize the impact of membrane lipids on endothelial Piezo1 activity. Completion of this project will foster collaboration between the two independent research teams and will support the concept that Piezo1 activity is dictated by lipid microenvironment. These studies will further establish a solid foundation that will lead to future independent funding (NIH R01 application), which will further our careers as independent scientists.

项目摘要： 脑血流量被精确控制以满足神经元的代谢需求。活跃的神经元向 血管通过多个神经血管耦合机制，以增加局部血流量的现象 称为功能性充血。充血反应增加了血流施加的摩擦力 微动脉和毛细血管的内皮细胞上。我们最近已经证明，Piezo 1通道是一个 它是脑毛细血管内皮细胞中至关重要的机械传感器，它介导Ca 2+信号， 机械刺激以前的研究主要集中在内皮细胞Piezo 1下游参与的机制 但是内皮细胞质膜流动性如何控制其活性仍然是未知的。响应 NIH特别关注通知（NOT-GM-23-034）“IDEA管理补充材料的可用性” 基金团队科学发展项目奖，“我们提供了令人信服的初步证据，脂质 富含胆固醇和磷酸肌醇的结构域存在于中枢神经系统毛细血管网络中。 此外，我们提出并提供了初步的结果，脂质影响Piezo 1活性。家长奖， 由NIGMS（P20 GM 135007）支持，提供了一个平台，以建立可持续的研究计划， 早期职业教师的特殊潜力，研究社会面临的重要健康问题：心血管 疾病、中风和认知障碍。这个团队科学提案旨在奠定基础和框架 Harraz博士（现任项目总监，P20 GM 135007）和冈萨雷斯博士（前任项目总监，P20 GM 130459） 在过去富有成效的合作基础上，将他们的专业知识和技术用于协同工作， 有影响力的生物学问题。在此，我们假设脂质胆固醇和磷脂酰肌醇-4，5- 二磷酸盐（PIP 2）在毛细血管网络中形成结构域，决定毛细血管内皮细胞膜的流动性 Piezo 1活性为了验证这一假设，拟议中的团队科学项目将使用各种最先进的 方法，包括膜片钳电生理技术和工程小鼠模型（Harraz Lab） 沿着高分辨率血管成像（冈萨雷斯实验室），以表征膜脂对 内皮细胞Piezo 1活性。该项目的完成将促进两个独立的 Piezo 1的活动是由脂质微环境决定的。这些 研究将进一步建立一个坚实的基础，这将导致未来的独立资助（NIH R 01申请）， 这将促进我们作为独立科学家的事业。

项目成果

Plasma Pro-Enkephalin A and Ischemic Stroke Risk: The Reasons for Geographic and Racial Differences in Stroke Cohort.

• DOI: 10.1016/j.jstrokecerebrovasdis.2021.106237
• 发表时间: 2022-03
• 期刊: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
• 作者: Short SA;Wilkinson K;Long DL;Judd S;Schulte J;Kissela BM;Howard G;Cushman M
• 通讯作者: Cushman M

Plasma Pro-Enkephalin A and Incident Cognitive Impairment: The Reasons for Geographic and Racial Differences in Stroke Cohort.

• DOI: 10.1161/jaha.122.029081
• 发表时间: 2023-06-06
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Short, Samuel A. P.;Wilkinson, Katherine;Schulte, Janin;Renteria, Miguel Arce;Cheung, Katharine L.;Nicoli, Charles D.;Howard, Virginia J.;Cushman, Mary
• 通讯作者: Cushman, Mary

Geographic disparities in cardiovascular mortality among patients with myelodysplastic syndromes: A population-based analysis.

骨髓增生异常综合征患者心血管死亡率的地理差异：基于人群的分析。

• DOI: 10.1016/j.canep.2022.102238
• 发表时间: 2022
• 期刊: Cancer epidemiology
• 影响因子: 2.6
• 作者: Adrianzen-Herrera,Diego;Sparks,AndrewD;Shastri,Aditi;Zakai,NeilA;Littenberg,Benjamin
• 通讯作者: Littenberg,Benjamin

The post-arteriole transitional zone: a specialized capillary region that regulates blood flow within the CNS microvasculature.

小动脉后过渡区：调节中枢神经系统微脉管系统内血流的特殊毛细血管区域。

• DOI: 10.1113/jp282246
• 发表时间: 2023
• 期刊: The Journal of physiology
• 作者: Mughal,Amreen;Nelson,MarkT;Hill-Eubanks,David
• 通讯作者: Hill-Eubanks,David

Piezo1 Is a Mechanosensor Channel in Central Nervous System Capillaries.

压电1是中枢神经系统毛细血管中的机械传感器通道。

• DOI: 10.1161/circresaha.122.320827
• 发表时间: 2022-05-13
• 期刊: CIRCULATION RESEARCH
• 影响因子: 20.1
• 作者: Harraz, Osama F.;Klug, Nicholas R.;Senatore, Amanda J.;Hill-Eubanks, David C.;Nelson, Mark T.
• 通讯作者: Nelson, Mark T.