Roles for Phospholipase D2 in metabolism and cardiovascular homeostasis

磷脂酶 D2 在代谢和心血管稳态中的作用

• 批准号: 8706676
• 负责人: Rochelle Nelson
• 金额: $ 4.27万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706676
• 关键词: Ablation; Acute; Address; Affect; Aldosterone; Amino Acid Substitution; Amino Acids; Angiotensin II; Angiotensin II Receptor; Antiatherogenic; Arginine; Atherosclerosis; Biological; Biological Assay; Blood Pressure; CD36 gene; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Cholesterol; Conflict (Psychology); Cysteine; Death Rate; Development; Diabetes Mellitus; Diet; Disease; Endocytosis; Enzymes; Family member; Fatty acid glycerol esters; Genetic; Genetic Polymorphism; Health; Homeostasis; Human; Hydrolysis; Hypertension; Individual; Investigation; Knowledge; Koreans; Laboratories; Lead; Lecithin; Life Expectancy; Ligands; Link; Lipids; Long-Term Effects; Low-Density Lipoproteins; Mediating; Membrane; Metabolic Diseases; Metabolism; Methods; Molecular; Mus; Obesity; Organism; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phase; Phenotype; Phosphatidic Acid; Phospholipase D; Physiological; Physiology; Plasmids; Platelet Activation; Play; Predisposition; Prevalence; Prevention; Process; Production; Protein Isoforms; Protein Overexpression; Receptor Signaling; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin-Aldosterone System; Reporting; Research; Risk Factors; Role; SR-B proteins; Second Messenger Systems; Signal Transduction; Signal Transduction Pathway; Single Nucleotide Polymorphism; Testing; Therapeutic; Training; Translating; Triglycerides; United States; Wild Type Mouse; Zona Glomerulosa; aortic arch; atheroprotective; attenuation; base; blood pressure regulation; cardiovascular disorder prevention; cardiovascular disorder risk; cohort; experience; genetic variant; in vivo; inhibitor/antagonist; macrophage; member; monocyte; novel strategies; phospholipase D2; prevent; public health relevance; receptor internalization; research study; second messenger; small molecule; tool; transcription factor; uptake

DESCRIPTION (provided by applicant): Classical members of the Phospholipase D (PLD) enzyme superfamily play essential roles in signal transduction pathways in many organisms. The most common enzymatic action undertaken by members of this superfamily is to generate the lipid second messenger phosphatidic acid through the hydrolysis of phosphatidylcholine. Cell biological studies have suggested many possible processes in which PLD family members might participate. On the organismal level, however, PLD's physiological and pathophysiological roles are in the early phases of investigation. Initial reports of mice lacking PLD isoforms have revealed phenotypes connected to platelet activation and receptor signaling. An intriguing possibility has arisen, though based on cell biological findings of studies on mice lacking the second isoform, PLD2, and human physiology linked to a PLD2 genetic variant. Taken together, I propose here to study PLD2's potential functions in cardiovascular homeostasis via regulation of plaque formation and blood pressure. Increased levels of circulating low density lipoproteins (LDL) and increased LDL accumulation by macrophages are major factors that leading to plaque formation and ultimately atherosclerosis. Peroxisome proliferator-activated receptor- ? (PPAR ?) is one of the major players in this process. Recent findings have proposed roles for PLD2 in the regulation of PPAR ?; studies now possible using PLD2-/- mice and macrophages in my sponsor's laboratory permit me to explore this relationship with new approaches. Aim 1 will focus on the susceptibility of PLD2-/- macrophages to lipid accumulation and PLD2-/- mice to plaque formation. Aim 2 will explore PLD2's potential contribution to the regulation of blood pressure via its involvement in the renin-angiotensin-aldosterone system. PLD2 has been proposed by my sponsor's lab to regulate endocytosis and signaling efficiency of the Angiotensin II receptor, and a PLD2 polymorphism in humans correlates with decreases in blood pressure. PLD2-/- mice and primary zona glomerulosa cells will be used to delineate the mechanism(s) by which PLD2 affects blood pressure. Ultimately, the knowledge gathered from these experiments will be beneficial to the growing understanding of the development of cardiovascular disease. These studies will also provide information necessary for new pharmacological targets aimed at the prevention of cardiovascular disease risk factors including hypertension and atherosclerosis.

描述（由申请人提供）：磷脂酶D（PLD）酶超家族的经典成员在许多生物体的信号转导途径中起着重要作用。该超家族成员采取的最常见的酶促作用是通过磷脂酰胆碱的水解产生脂质二信使磷脂酸。细胞生物学研究表明，PLD家族成员可能参与的许多可能的过程。然而，在生物水平上，PLD的生理和病理生理作用在研究的早期阶段。缺乏PLD同工型的小鼠的初步报道揭示了与血小板激活和受体信号相关的表型。尽管基于缺乏与PLD2遗传变异有关的第二种同工型，PLD2和人类生理学的小鼠的研究细胞生物学发现，但出现了一种有趣的可能性。综上所述，我在这里建议通过调节斑块形成和血压来研究PLD2在心血管稳态中的潜在功能。循环低密度脂蛋白（LDL）的水平增加和巨噬细胞的LDL积累增加是导致牙菌斑形成并最终导致动脉粥样硬化的主要因素。过氧化物酶体增殖物激活的受体？ （PPAR？）是此过程中的主要参与者之一。最近的发现提出了PLD2在PPAR调节中的作用？现在可以在赞助商的实验室中使用PLD2 - / - 小鼠和巨噬细胞进行研究，这使我能够通过新方法探索这种关系。 AIM 1将集中于PLD2 - / - 巨噬细胞对脂质积累的敏感性以及PLD2 - / - 小鼠对斑块形成的敏感性。 AIM 2将通过参与肾素 - 血管紧张素 - 醛固酮系统来探索PLD2对血压调节的潜在贡献。我的赞助商实验室提出了PLD2，以调节血管紧张素II受体的内吞和信号传导效率，而人类中的PLD2多态性与血压降低相关。 PLD2 - / - 小鼠和原代Zona肾小球细胞将用于描述PLD2影响血压的机制。最终，从这些实验中收集的知识将有助于对心血管疾病发展的不断理解。这些研究还将提供旨在预防心血管疾病危险因素在内的新药理目标所需的信息，包括高血压和动脉粥样硬化。