Pannexin Channels In Vascular Physiology & Inflammation

血管生理学中的 Pannexin 通道

• 批准号: 10625317
• 负责人: Douglas A. Bayliss
• 金额: $ 243.63万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625317
• 关键词: Address; Adipocytes; Airway Disease; Anti-Inflammatory Agents; Apoptotic; Arterial Fatty Streak; Biology; Blood Vessels; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell membrane; Cell physiology; Cells; Collaborations; Communication; Data; Diabetes Mellitus; Diet; Disease; Environment; Equilibrium; Excision; Extracellular Space; Fibrosis; Funding; Health; Homeostasis; Human; Hypertension; Individual; Inflammation; Inflammatory; Influentials; Interphase; Ion Channel; Ions; Learning; Link; Lipids; Liver; Liver Fibrosis; Lymphocyte; Macrophage; Mediating; Membrane Transport Proteins; Metabolic; Metabolic Diseases; Metabolic syndrome; Molecular; Myocardial Infarction; Neighborhoods; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Pathologic; Pathology; Patients; Phagocytes; Pharmacologic Substance; Phase; Physiological; Physiological Processes; Physiology; Pre-Clinical Model; Predisposition; Program Research Project Grants; Proteins; Publications; Purine Nucleotides; Regulation; Resistance; Respiratory Disease; Respiratory System; Risk; Role; Series; Signal Transduction; Site; Smooth Muscle Myocytes; Sympathetic Nervous System; Syndrome; System; Testing; Therapeutic; Tissues; Vascular Diseases; Vascular Smooth Muscle; Work; airway inflammation; blood pressure control; blood pressure regulation; body system; cardiometabolism; cell type; combat; extracellular; genome-wide; human disease; insight; intercellular communication; interest; mortality; mouse model; nervous system disorder; novel; novel therapeutics; pharmacologic; programs; recruit; small molecule; stem; therapeutic target; treatment strategy; vasoconstriction

OVERALL PROJECT SUMMARY Inter-cellular communication between cells within a tissue environment is fundamentally important for many physiological processes. Channels and transmembrane transporters that conduct ions and other molecules across the plasma membrane in healthy living cells are also linked to pathologies of the cardiovascular and respiratory systems. Extracellular nucleltides (such as ATP) and their derivatives, as well as other metabolites critically influence many aspects of vasculary physiology such as sympthetic nerve-induced vasoconstriction and blood pressure regulation, as well disease states such as diet-induced cardiometabolic syndromes. Recent exciting series of observations suggest that the pannexin proteins form channels on the plasma membrane, and by permeating ions and/or the release of nucleotides in a very regulated manner, these pannexin channels allow cells to communicate with other cells. Consistent with this, altered expression of pannexin channels have been linked to cardovascular and metabolic disorders. Independently, the pannexin channels also play a role in releasing nucleotides from early stage apoptotic cells that appear critical for communicating with phagocytes, and with the tissue microenvironment. The central hypothesis tested via this PO1 application is that pannexin channels sit at a critical interphase between normal homeostasis within the cardiovascular system, and the disease states leading inflammation, and hypertension. The four projects that comprise this proposal address the role of pannexin channels as follows. Project 1 (Ravichandran) addresses the role of pannexin channels in apoptotic cell:phagocyte communication, between dying cells and the neighborhood in regulating anti- inflammatory signaling, and regulating tissue inflammation; Project 2 (Isakson) addresses how pannexin channels in vascular smooth muscle cells contribute to vasoconstriction in resistance vessels to regulate blood pressure, and how Pannexin 1 links sympathetic nervous system to arterial function; Project 3 (Leitinger) addresses how pannexin channels regulate inflammation and fibrosis of the liver as part of the larger cardiometabolic syndrome; Project 4 (Bayliss) addresses molecular mechanisms of pannexin channel activation in physiological and diseased states. With the combination of mouse models and ex vivo studies, and mechanistic approaches, and identification of new compounds capable of altering Panx1 function, we expect to provide exciting new insights on pannexin channels and purinergic signaling in vascular physiology and hypertension, and the basis for novel treatment strategies targeting the regulated opening and closing of these channels in specific disease states. We expect our studies have a broad impact to cardiovascular, metabolic, and and respiratory diseases.

项目总体概要 组织环境内细胞之间的细胞间通讯对于许多人来说至关重要 生理过程。传导离子和其他分子的通道和跨膜转运蛋白 健康活细胞中的质膜穿越也与心血管和心血管疾病有关 呼吸系统。胞外核苷酸（如ATP）及其衍生物，以及其他代谢物 严重影响血管生理学的许多方面，例如交感神经诱导的血管收缩和 血压调节，以及饮食引起的心脏代谢综合征等疾病状态。最近的 一系列令人兴奋的观察结果表明，pannexin 蛋白在质膜上形成通道，并且 通过以非常受调节的方式渗透离子和/或释放核苷酸，这些pannexin通道允许 细胞与其他细胞进行通讯。与此一致的是，pannexin 通道的表达发生了改变 与心血管和代谢紊乱有关。独立地，pannexin 通道也发挥作用 从早期凋亡细胞中释放核苷酸，这些核苷酸对于与吞噬细胞的通讯至关重要， 以及组织微环境。通过此 PO1 应用测试的中心假设是 pannexin 通道位于心血管系统内正常稳态与 导致炎症和高血压的疾病状态。构成该提案的四个项目地址 Pannexin通道的作用如下。项目 1 (Ravichandran) 探讨了 pannexin 通道在 凋亡细胞：吞噬细胞通讯，在死亡细胞和邻近细胞之间调节抗凋亡 炎症信号传导和调节组织炎症；项目 2 (Isakson) 解决 pannexin 如何 血管平滑肌细胞中的通道有助于阻力血管收缩以调节血液 压力，以及 Pannexin 1 如何将交感神经系统与动脉功能联系起来；项目 3（雷廷格） 解决了pannexin通道如何调节肝脏的炎症和纤维化作为更大的一部分 心脏代谢综合征；项目 4（Bayliss）解决 pannexin 通道激活的分子机制 在生理和疾病状态下。结合小鼠模型和离体研究， 机制方法以及能够改变 Panx1 功能的新化合物的鉴定，我们期望 提供关于血管生理学中的泛联蛋白通道和嘌呤能信号传导的令人兴奋的新见解 高血压，以及针对这些调节打开和关闭的新治疗策略的基础 特定疾病状态下的通道。我们期望我们的研究对心血管、代谢、 和呼吸道疾病。

项目成果

Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes.

• DOI: 10.1016/j.molmet.2015.06.009
• 发表时间: 2015-09
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Adamson SE;Meher AK;Chiu YH;Sandilos JK;Oberholtzer NP;Walker NN;Hargett SR;Seaman SA;Peirce-Cottler SM;Isakson BE;McNamara CA;Keller SR;Harris TE;Bayliss DA;Leitinger N
• 通讯作者: Leitinger N

Redox-Regulation of α-Globin in Vascular Physiology.

• DOI: 10.3390/antiox11010159
• 发表时间: 2022-01-14
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Kiger L;Keith J;Freiwan A;Fernandez AG;Tillman H;Isakson BE;Weiss MJ;Lechauve C
• 通讯作者: Lechauve C

A high-conductance chemo-optogenetic system based on the vertebrate channel Trpa1b.

• DOI: 10.1038/s41598-017-11791-z
• 发表时间: 2017-09-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Lam PY;Mendu SK;Mills RW;Zheng B;Padilla H;Milan DJ;Desai BN;Peterson RT
• 通讯作者: Peterson RT

Phagocytic clearance of dying cells and its implications.

死亡细胞的吞噬清除及其影响。

• DOI: 10.1111/imr.13285
• 发表时间: 2023
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Ravichandran,KodiS

Extracellular vesicles and insulin-mediated vascular function in metabolic syndrome.

• DOI: 10.14814/phy2.15530
• 发表时间: 2023-01
• 期刊: Physiological reports
• 影响因子: 2.5