PGI2 restrains immunopathogenesis in hypertension

PGI2 抑制高血压的免疫发病机制

基本信息

项目摘要

PROJECT SUMMARY Hypertension is a disease defined as blood pressure that is greater than 130/80mmHg. Hypertension contributes significantly to cardiovascular disease morbidity and mortality. While the importance of blood pressure control has become abundantly clear, we are still far from understanding the true etiology of hypertension. In recent years, inflammation was determined to play a causal role in hypertension. Specifically, immune cells invade target organs during the course of the disease and release cytokines that cause end- organ damage. Several studies have determined antigen presentation by dendritic cells (DCs) and monocytes is important for initiation of hypertension. In addition, pro-inflammatory T cells perpetuate the disease. Anti- inflammatory T regulatory cells (Treg) can control the hypertensive response. Interestingly, evidence suggests that long-lasting use of cyclooxygenase inhibitors, which prevent metabolism of arachidonic acid (AA) to prostaglandins and thromboxane, increases blood pressure. Prostaglandin I2 (PGI2) is an AA metabolite that our laboratory has determined has immunomodulatory effects. Our group has demonstrated that PGI2 acts to directly inhibit the functionality of pro-inflammatory DCs and CD4+ Th1 and Th2 cells, while promoting the function of tolerogenic DCs. However, the impact of PGI2 on the functionality of immune cells in hypertension is unknown. A previous study has demonstrated that mice deficient in the receptor for PGI2, IP, develop elevated blood pressure in response to high salt diet, suggesting that PGI2 signaling is important for controlling blood pressure elevation in response to stimuli. Further, I have preliminary data which suggests that PGI2 controls the inflammatory response to hypertensive stimuli. Specifically, mice deficient in IP have increased infiltration of T cells into their aortas compared to wild-type (WT) mice in response to angiotensin II (Ang II). In addition, infusion of the PGI2 analog treprostinil during the course of Ang II infusion prevents the infiltration of T cells, monocytes/macrophages and DCs into the aorta of WT mice compared to WT mice that received Ang II and the vehicle for treprostinil. Thus, these recent studies and my preliminary data lead me to hypothesize that PGI2 promotes anti-inflammatory responses during hypertension. To test this hypothesis we will use mouse models of hypertension and primary cells from normotensive and hypertensive mice and humans to: Aim 1 (K99): Test the hypothesis that PGI2 promotes Treg function and stability during hypertension, thereby counteracting pro-inflammatory subsets of T cells; and Aim 2 (R00): Test the hypothesis that PGI2 restrains pro-inflammatory DC and promotes tolerogenic DC function during hypertension. Determining the mechanisms by which PGI2 controls the immune response to hypertension will greatly advance the field and result in new therapeutic directions for the treatment of hypertension. These proposed studies, along with my proposed career development plan, will provide a foundation for my career as an independent investigator in an outstanding environment.
项目总结

项目成果

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Allison Elizabeth Norlander其他文献

Allison Elizabeth Norlander的其他文献

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{{ truncateString('Allison Elizabeth Norlander', 18)}}的其他基金

PGI2 restrains immunopathogenesis in hypertension
PGI2 抑制高血压的免疫发病机制
  • 批准号:
    10731402
  • 财政年份:
    2023
  • 资助金额:
    $ 13.8万
  • 项目类别:
PGI2 restrains immunopathogenesis in hypertension
PGI2 抑制高血压的免疫发病机制
  • 批准号:
    10447208
  • 财政年份:
    2021
  • 资助金额:
    $ 13.8万
  • 项目类别:
The Effect of Salt on T Cell Function in Hypertension
盐对高血压患者 T 细胞功能的影响
  • 批准号:
    9138616
  • 财政年份:
    2015
  • 资助金额:
    $ 13.8万
  • 项目类别:
The Effect of Salt on T Cell Function in Hypertension
盐对高血压患者 T 细胞功能的影响
  • 批准号:
    8908297
  • 财政年份:
    2015
  • 资助金额:
    $ 13.8万
  • 项目类别:

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