Roles for Phospholipase D2 in metabolism and cardiovascular homeostasis

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发挥重要作用。该超家族成员最常见的酶促作用是通过磷脂酰胆碱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，在机体水平上，PLD的生理和病理生理作用尚处于研究的早期阶段。缺乏PLD亚型的小鼠的初步报告揭示了与血小板激活和受体信号传导相关的表型。一种有趣的可能性已经出现，尽管基于缺乏第二种同种异构体PLD2的小鼠的细胞生物学研究结果，以及与PLD2遗传变异相关的人类生理学。综上所述，我建议研究PLD2通过调节斑块形成和血压在心血管稳态中的潜在功能。循环低密度脂蛋白（LDL）水平升高和巨噬细胞LDL积累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-γ (PPARγ)是这一过程中的主要参与者之一。最近的研究发现提出了PLD2在调控PPARγ中的作用；在我的赞助商的实验室中，现在可以使用PLD2-/-小鼠和巨噬细胞进行研究，这使我能够用新的方法探索这种关系。目的1将关注PLD2-/-巨噬细胞对脂质积累的易感性以及PLD2-/-小鼠对斑块形成的易感性。目的2将探讨PLD2通过参与肾素-血管紧张素-醛固酮系统对血压调节的潜在贡献。我的赞助人的实验室已经提出PLD2调节血管紧张素II受体的内吞作用和信号传导效率，并且人类PLD2多态性与血压降低相关。PLD2-/-小鼠和原发性肾小球带细胞将被用来描述PLD2影响血压的机制。最终，从这些实验中收集到的知识将有助于加深对心血管疾病发展的理解。这些研究还将为预防心血管疾病危险因素（包括高血压和动脉粥样硬化）的新药理靶点提供必要的信息。

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-γ (PPARγ) is one of the major players in this process. Recent findings have proposed roles for PLD2 in the regulation of PPARγ; 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.