Nitric Oxide Deficiency in Hypertensive Nephropathies

高血压肾病中的一氧化氮缺乏

基本信息

  • 批准号:
    8698278
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-04-01 至 2016-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Hypertension is the second leading primary cause of end-stage renal disease; however, considerable variation exists with respect to the relative risk of hypertensive-induced renal damage in the veteran population. The factors that alter the susceptibility to hypertensive renal injury as well as the underlying mechanisms remain poorly understood. One of the difficulties in investigating the mechanisms that contribute to hypertensive renal injury is the wide spectrum of pathology observed in hypertensive patients with kidney damage. The two major pathophysiologic mechanisms thought to contribute to the pathogenesis and progression of hypertensive renal injury include local exposure to excessive pressures with resulting barotrauma and chronic ischemia with resulting hypoxia. While both mechanisms will contribute to the progression of renal injury, the relative contribution of barotrauma and ischemia to the observed injury likely differs among hypertensive individuals depending on the underlying pathophysiologic context and the presence of additional genetic or environmental risk factors. One such risk factor that is thought to alter the susceptibility to hypertensive renal injury is endothelial dysfunction with reduced levels of nitric oxide (NO). Reduced NO levels have been reported in human populations susceptible to an accelerated progression of hypertensive renal injury, such as African- Americans and individuals with chronic kidney disease. Yet, the role of NO availability on the relative contribution of BP dependent and independent pathways of renal injury, its effects on pathways of barotrauma vs. ischemia induced injury, and the underlying mechanisms remain poorly understood. In the studies proposed in this career development application, we will utilize groups of rats and mice with differences in NO availability as a broad model system to investigate the mechanisms by which reduced NO levels alter the susceptibility to hypertensive injury. We will perform these studies in two models of hypertension in which the pathogenesis of renal injury is thought to be predominantly mediated via barotrauma vs. ischemia pathways. These studies are of clinical significance and should lead to very novel insights regarding the mechanisms by which NO availability alters the susceptibility barotrauma and ischemia mediated pathways of renal injury during the pathogenesis and progression of hypertension. Studies in Aim 1 will focus on the temporal evolution of renal injury, several indices of NO availability, oxidative stress, and purported cellular mediators of injury (i.e., hypoxia, osteopontin, etc.). Dietary interventions will be used to alter the level of NO availability to determine the importance of NO in ameliorating renal injury in various hypertensive states. Studies in Aim 2 are focused on the potential BP dependent and independent mechanisms by which reduced NO availability may enhance the susceptibility to hypertensive renal injury. These studies will focus on the pressor and nonpressor effects of NO availability on the regulation of renal hemodynamics, renal function, and renal oxygenation levels during the pathogenesis and progression of hypertensive renal injury. The studies in Aim 3 will investigate the relative contribution of endothelial dependent and independent pathways in isolated mesenteric arteries to improve our understanding of the mechanisms contributing to the differences in NO availability between the experimental animals. In addition to the novel and clinically relevant set of research experiments, there are numerous informal and formal training activities that should prepare the applicant for an independent career in academic medicine. Furthermore, the proposed studies should also lead to several novel and relevant areas of research, which are independent of his mentoring group, which the applicant can pursue for independent funding.
描述(由申请人提供): 高血压是终末期肾病的第二大主要原因;然而,在退伍军人人群中,高血压诱导的肾损伤的相对风险存在相当大的差异。改变高血压肾损伤易感性的因素以及潜在的机制仍然知之甚少。研究高血压肾损伤机制的困难之一是在高血压肾损伤患者中观察到的广泛的病理变化。两个主要的病理生理机制被认为有助于高血压肾损伤的发病机制和进展,包括局部暴露于过高的压力,导致气压伤和慢性缺血,导致缺氧。虽然这两种机制都有助于肾损伤的进展,但气压伤和缺血对所观察到的损伤的相对贡献可能在高血压个体中不同,这取决于潜在的病理生理背景和其他遗传或环境风险因素的存在。一个这样的风险因素,被认为是改变高血压肾损伤的易感性是内皮功能障碍与一氧化氮(NO)水平降低。据报道,在易受高血压肾损伤加速进展影响的人群中,如非裔美国人和患有慢性肾病的个体,NO水平降低。然而,NO的可用性的作用的相对贡献的BP依赖性和独立的途径的肾损伤,其对气压创伤与缺血诱导的损伤的途径的影响,和潜在的机制仍然知之甚少。在这项职业发展申请中提出的研究中,我们将利用NO可用性差异的大鼠和小鼠组作为一个广泛的模型系统来研究NO水平降低改变高血压损伤易感性的机制。我们将在两种高血压模型中进行这些研究,其中肾损伤的发病机制被认为主要是通过气压伤与缺血途径介导的。这些研究具有临床意义,并应导致非常新颖的见解的机制,NO的可用性改变的易感性气压伤和缺血介导的途径,肾损伤的发病机制和进展过程中的高血压。目的1中的研究将集中于肾损伤的时间演变、NO可用性的几个指标、氧化应激和据称的损伤细胞介质(即,缺氧、骨桥蛋白等)。饮食干预将被用来改变NO的可用性水平,以确定NO在改善各种高血压状态下的肾损伤的重要性。目的2中的研究集中于潜在的BP依赖性和非依赖性机制,通过该机制,降低的NO可用性可增强高血压肾损伤的易感性。这些研究将集中在高血压肾损伤的发病机制和进展过程中,NO的可用性对肾脏血流动力学,肾功能和肾氧合水平的调节的升压和非升压作用。目的3中的研究将研究离体肠系膜动脉中内皮依赖性和非依赖性途径的相对贡献,以提高我们对实验动物之间NO可用性差异的机制的理解。除了新颖和临床相关的研究实验外,还有许多非正式和正式的培训活动,应该为申请人在学术医学领域的独立职业做好准备。此外,拟议的研究还应导致几个新的和相关的研究领域,这是独立于他的指导小组,申请人可以追求独立的资金。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Aaron James Polichnowski其他文献

Aaron James Polichnowski的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Aaron James Polichnowski', 18)}}的其他基金

Hemodynamic mechanisms of impaired recovery and progression of renal disease following AKI in preexisting CKD states
既往 CKD 状态下 AKI 后肾病恢复受损和进展的血流动力学机制
  • 批准号:
    10046795
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Nitric Oxide Deficiency in Hypertensive Nephropathies
高血压肾病中的一氧化氮缺乏
  • 批准号:
    8141917
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Nitric Oxide Deficiency in Hypertensive Nephropathies
高血压肾病中的一氧化氮缺乏
  • 批准号:
    8402118
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Nitric Oxide Deficiency in Hypertensive Nephropathies
高血压肾病中的一氧化氮缺乏
  • 批准号:
    8263684
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
  • 批准号:
    484000
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Operating Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了