Roles for Phospholipase D2 in metabolism and cardiovascular homeostasis

描述(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发挥着重要作用。这个超家族的成员最常见的酶作用是通过磷脂酰胆碱的水解产生脂质第二信使磷脂酸。细胞生物学研究表明，PLD家族成员可能参与了许多可能的过程。然而，在生物体水平上，PLD的生理和病理生理学作用还处于研究的早期阶段。最初关于缺乏PLD亚型的小鼠的报告揭示了与血小板激活和受体信号转导有关的表型。一种有趣的可能性已经出现，尽管基于对缺乏第二种亚型PLD2的小鼠的细胞生物学研究结果，以及与PLD2基因变体相关联的人类生理学。综上所述，我建议在此研究PLD2‘S通过调节斑块形成和血压在心血管内稳态中的潜在作用。循环低密度脂蛋白水平升高和巨噬细胞低密度脂蛋白蓄积增加是导致斑块形成和最终动脉粥样硬化的主要因素。过氧化物酶体增殖物激活受体？(PPAR？)是这一过程中的主要参与者之一。最近的发现表明PLD2在调节PPAR？中的作用；现在在我的赞助者的实验室中使用PLD2-/-小鼠和巨噬细胞进行的研究允许我用新的方法来探索这种关系。目的1将重点放在PLD2-/-巨噬细胞对脂质堆积的敏感性和PLD2-/-小鼠对斑块形成的敏感性。目的2探讨PLD2的S通过参与肾素-血管紧张素-醛固酮系统在血压调节中的潜在作用。PLD2是由我的赞助人的实验室提出的，用来调节血管紧张素II受体的内吞作用和信号效率，而人类的PLD2基因多态性与血压下降有关。PLD2-/-小鼠和原代肾小球细胞将被用来描述PLD2影响血压的机制(S)。最终，从这些实验中收集的知识将有助于加深对心血管疾病发展的了解。这些研究还将为旨在预防包括高血压和动脉粥样硬化在内的心血管疾病危险因素的新的药理目标提供必要的信息。

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.