Monocyte P311 Expression Level as Predictor of Hypertension in Mice

单核细胞 P311 表达水平作为小鼠高血压的预测因子

• 批准号: 7814384
• 负责人: Lucia Schuger
• 金额: $ 50万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7814384
• 关键词: Age; Animals; Aorta; Biological Markers; Blood Pressure; Blood Vessels; Blood specimen; Brain; Brain Part; Clinical; Development; Down-Regulation; Echocardiography; Evaluation; Experimental Models; Female; Future; Genetic; Goals; Human; Hypertension; Hypotension; Immunoblotting; Leukocytes; Mesenteric Arteries; Messenger RNA; Microscopic; Molecular; Mus; Myofibroblast; Myosin Light Chains; Neurons; Outcome; Phosphorylation; Play; Predisposition; Protein Family; Proteins; Protocols documentation; Reading; Research; Role; Severities; Staging; Telemetry; Testing; Time; Transgenic Mice; Translations; Vascular Smooth Muscle; base; healthy volunteer; male; monocyte; normotensive; novel therapeutic intervention; overexpression; peripheral blood; public health relevance; research study; response; sex; wound

DESCRIPTION (provided by applicant): P311 is an 8 kDa intracellular protein highly conserved across species. P311 does not belong to any established protein family; neither has signature motifs that could suggest function. In mouse and human P311 is produced in the brain, in vascular smooth muscle [11, 24], in wound myofibroblasts [11] and their precursors, the pre-myofibroblasts [11]; and in blood monocytes (research plan, figures 5 and 7). By performing telemetry studies we recently found that p311-deficient mice (P311 KOs) have pronounced systemic systolic and diastolic hypotension, without overt gross or microscopic vascular abnormalities. Echocardiographic, morphometric and myosin light chain 20 (MLC20) phosphorylation studies indicated that the hypotension is due to a decrease in vascular tone rather than the result of a vascular structural abnormality. Hypotension is accompanied by a significant downregulation in vascular TGF-¿1 level and activity, which occurs at the translation and/or degradation stage. More importantly, P311 KOs were significantly protected against the development of uninephrectomy-DOCA-induced hypertension. Pertinent to the Challenge Topic selected, additional studies showed a stable and tight correlation between vascular and monocyte P311 expression but a significant difference in P311 expression was observed between mice with different genetic background, such that CD-1 mice express over 2-fold less P311 than the BL/6 strain. Significant differences in monocyte P311 expression were also observed between human healthy volunteers. Since lack of P311 ameliorated experimentally-induced hypertension, we compared the hypertensive response in mice with low (CD-1) and high (BL/6) monocytic P311 level. This preliminary study showed that while both groups were normotensive under baseline conditions, the mice with low P311 developed significantly less severe hypertension than the mice with high P311 level (p<0.0001). Based on these preliminary observations we hypothesize that P311 plays an important role in the modulation of systemic blood pressure and that the level of P311 in peripheral blood monocytes is a useful biomarker to predict susceptibility for the development and/or severity of future hypertension. To test these hypotheses, the specific aims of this proposal are: 1. To determine whether P311 expression level and its vascular-monocyte correlation, observed in preliminary studies, change according to age and sex. 2. To determine whether the baseline level of monocyte/vascular P311 expression correlates with the severity of experimentally-induced hypertension, as suggested by preliminary studies. 3. To determine whether vascular P311 overexpression causes hypertension and/or increases the severity of experimentally-induced hypertension. The experiments proposed in aim #1 will demonstrate whether P311 level of expression in blood vessels and monocytes depends on the mice genetic background, whether it changes over time in male and female mice of same genetic background and whether its vascular level can be accurately assessed by determining P311 mRNA level in peripheral blood monocytes. The full scale experiments proposed in aim #2 and part of aim #3 will hopefully validate and expand our preliminary studies by unequivocally demonstrating that the basal P311 expression level in mice directly correlates with the hypertensive response in an experimental model of induced hypertension. If the studies proposed in aim #1 and #2 yield the expected outcomes, we could conclude that P311 expression level in monocytes can be accurately determined and represents a reliable predictor of hypertension susceptibility in mice. In such a case, the clinical usefulness of P311 as a biomarker for human susceptibility to hypertension should warrant direct exploration. Finally, the experiments proposed in aim #3 will demonstrate whether, at least in mice, high P311 levels can play a causative/contributory role in hypertension. In such a case, P311 could represent an additional target for the development of novel therapeutic approaches. PUBLIC HEALTH RELEVANCE: P311 is an 8 kDa intracellular protein of unknown function. In humans and mice P311 is produced by certain neurons, by vascular smooth muscle and by monocytes (a type of white blood cell). Based on preliminary studies, the main goal of this project is to demonstrate that baseline P311 level in blood monocytes represents a useful biomarker to predict the future development and/or severity of hypertension in mice.

描述（由适用提供）：p311是一个高度构成在物种之间的8 kDa细胞内蛋白。 P311不属于任何已建立的蛋白质家族。两个都没有可以暗示功能的标志性主题。在小鼠和人类的p311中，在大脑中，血管平滑肌[11，24]中产生，在伤口肌纤维细胞中[11]及其前体，肌纤维细胞前的前体[11]；在血液单核细胞中（研究计划，图5和7）。通过进行遥测研究，我们最近发现P311缺陷小鼠（P311 KOS）明显具有全身收缩压和舒张性低血压，没有明显的总或显微镜血管异常。超声心动图，形态计量学和肌球蛋白轻链20（MLC20）磷酸化研究表明，低血压是由于血管张力降低而不是血管结构异常的结果。低血压伴随着在翻译和/或降解阶段发生的血管TGF-€1水平和活性的显着下调。更重要的是，P311 KO受到明显的保护，以防止单次切除术诱导的高血压的发展。与所选的挑战主题有关，其他研究表明，血管和单核细胞p311表达之间存在稳定且紧密的相关性，但是在具有不同遗传背景的小鼠之间观察到p311表达的显着差异，因此CD-1小鼠表现出比BL/6菌株低2倍的p311。人类健康志愿者之间也观察到单核细胞p311表达的显着差异。由于缺乏p311可以改善实验诱导的高血压，因此我们比较了低（CD-1）和高（BL/6）单核细胞p311水平的小鼠的高血压反应。这项初步研究表明，尽管两组在基线条件下都是正常的，但p311较低的小鼠的严重高血压明显低于p311水平高的小鼠（p <0.0001）。基于这些初步观察，我们假设p311在系统性血压调节中起重要作用，并且外周血单核细胞中的p311水平是预测对未来高血压发育和/或严重程度的敏感性的有用生物标志物。为了检验这些假设，该提案的具体目的是：1。确定p311表达水平及其血管 - 单细胞相关性是否在初步研究中观察到，根据年龄和性别发生了变化。 2。确定单核细胞/血管p311表达的基线水平是否与实验诱导的高血压的严重程度相关，如初步研究所示。 3。确定血管p311是否会导致高血压和/或增加实验诱导的高血压的严重程度。 AIM＃1中提出的实验将证明血管和单核细胞中p311表达水平是否取决于小鼠的遗传背景，是否在相同遗传背景的男性和雌性小鼠中随时间变化以及是否可以通过确定双胸血单核细胞中的P311 mRNA水平来准确评估其血管水平。 AIM＃2和AIM＃3的一部分提出的全尺度实验将有望通过明确证明小鼠中基本的p311表达水平与诱导高血压实验模型中的高血压反应直接相关的基本p311表达水平来验证和扩展我们的初步研究。如果在AIM＃1和＃2中提出的研究产生了预期的结果，则可以准确确定单核细胞中的P311表达水平，并代表小鼠高血压易感性的可靠预测指标。在这种情况下，p311作为人类对高血压敏感性的生物标志物的临床实用性应需要直接探索。最后，AIM＃3中提出的实验将证明至少在小鼠中，高P311水平是否可以在高血压中起因果/贡献作用。在这种情况下，P311可以代表开发新型治疗方法的附加目标。 公共卫生相关性：p311是一种8 kDa功能的细胞内蛋白质。在人类和小鼠中，p311由某些神经元，血管平滑肌和单核细胞（一种白细胞）产生。基于初步研究，该项目的主要目标是证明血液单核细胞中的基线p311水平代表了一种有用的生物标志物，以预测小鼠中高血压的未来发展和/或严重程度。