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： 精确控制脑血流以满足神经元代谢需求。主动神经元向 通过多种神经血管耦合机制进行脉管系统，以增加现象中的区域血流 称为功能性充血。血症反应增加了血流施加的摩擦力 进入动脉和毛细血管的内皮细胞。我们最近证明了Piezo1频道是一个 脑毛细血管内皮细胞中的关键机理经验指标，并介导Ca2+信号响应于 机械刺激。先前的研究重点是内皮压电下游参与的机制 激活，但是内皮细胞质膜流动性如何控制其活性仍然未知。作为回应 向NIH发出特殊关注的通知（INT-GM-23-034） 为团队科学发展项目提供资金的奖项，“我们提供了令人信服的初步证据 中枢神经系统毛细血管网络中存在富含胆固醇和磷酸肌醇的结构域。 此外，我们提出并提供了脂质影响压电活动的初步结果。父母奖， 在NIGMS（P20GM135007）的支持下，提供了一个平台来构建以 早期职业教师研究社会面临的重要健康问题的杰出潜力：心血管 疾病，中风和认知障碍。该团队科学建议旨在奠定基础和框架 对于博士。 Harraz（现任项目总监P20GM135007）和Gonzales（前项目总监，P20GM130459） 以他们过去的富有成效的合作为基础，并将其专业知识和技术带入协同工作 有影响力的生物学问题。本文中，我们假设脂质胆固醇和磷脂酰肌醇4,5-- 毛细管网络中的双磷酸（PIP2）形成域，这些结构域确定毛细管内皮膜流动性 和压电活动。为了检验这一假设，拟议的团队科学项目将使用潜水员，最先进的 方法，包括贴片钳电生理技术和工程小鼠模型（Harraz Lab） 以及高分辨率的血管成像（Gonzales Lab），以表征膜脂质对 内皮压电1活性。该项目的完成将促进两个独立 研究团队将支持Piezo1活动由脂质微环境决定的概念。这些 研究将进一步建立坚实的基础，该基础将导致未来的独立资金（NIH R01应用）， 这将进一步作为独立科学家的职业。

项目成果

Piezo1 Is a Mechanosensor Channel in Central Nervous System Capillaries.

• 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.

Microtubule destabilization with colchicine increases the work output of myocardial slices.

秋水仙碱的微管不稳定增加了心肌切片的功输出。

• DOI: 10.1016/j.jmccpl.2024.100066
• 发表时间: 2024
• 期刊: Journal of molecular and cellular cardiology plus
• 作者: Hancock,EmmaleighN;Palmer,BradleyM;Caporizzo,MatthewA
• 通讯作者: Caporizzo,MatthewA

Interleukin-6, Diabetes, and Metabolic Syndrome in a Biracial Cohort: The Reasons for Geographic and Racial Differences in Stroke Cohort.

双种族队列中的白细胞介素 6、糖尿病和代谢综合征：中风队列中地理和种族差异的原因。

• DOI: 10.2337/dc23-0914
• 发表时间: 2024
• 期刊: Diabetes care
• 影响因子: 16.2
• 作者: Palermo,BrittneyJ;Wilkinson,KatherineS;Plante,TimothyB;Nicoli,CharlesD;Judd,SuzanneE;KaminMukaz,Debora;Long,DLeann;Olson,NelsC;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