Age and Control of Human Skin Flow

人类皮肤流动的年龄和控制

基本信息

  • 批准号:
    7714026
  • 负责人:
  • 金额:
    $ 37.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1987
  • 资助国家:
    美国
  • 起止时间:
    1987-09-30 至 2014-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Humans over the age of 65 contribute disproportionately to cold- and heat-related morbidities and mortalities and the relative risk of death from all causes increases during cold and hot weather. Because core temperature excursions during even mild heating or cooling (i.e., in the absence of shivering or sweating) are greater in the elderly, altered vasomotor regulation is the seminal age-related deficit. Recently we have examined the mechanisms of age-related attenuated reflex cutaneous vasoconstriction (VC) and vasodilation (VD). This attenuated reflex cutaneous vasoreactivity in aged skin is due to a functional loss of adrenergic VC and active cholinergic VD co-transmitter(s), and altered downstream vascular signaling including (1) adrenergic desensitization, and (2) decreased nitric oxide (NO) availability. The logical extension of that work, supported by provocative preliminary and pilot data, is to examine the role of oxidant-induced reduced tetrahydrobiopterin (BH4) bioavailability in the aged cutaneous vasculature. Human aging is associated with increased in oxidant stress leading to the destruction of the critical enzymatic cofactor BH4. BH4 is ubiquitous throughout neural and vascular tissues and has emerged as a viable molecular target that may underlie both attenuated reflex cutaneous VC and VD mechanisms. Age-related deficiencies in BH4 appear to play a central role in attenuated reflex cutaneous VC. In adrenergic nerve terminals, BH4 is required for the synthesis and packaging of catecholamines by serving as a critical cofactor for tyrosine hydroxylase and by maintaining the enzyme in its reduced active form. In Specific Aim 1 we will examine the role of reduced BH4 bioavailability in attenuated reflex VC in aged skin using physiological and pharmacological stimuli in separate experiments to induce sympathetic VC. BH4 is also an essential cofactor for the NO-synthase (NOS) isoforms which are necessary for the full expression of reflex cutaneous VD. NOS uncouples during substrate and/or oxidant-induced BH4 deficiencies resulting in superoxide production. Increasing substrate availability for NOS and/or providing supraphysiological doses of ascorbate augments NO-dependent VD in aged human skin. Because of the putative role of substrate availability in NOS uncoupling, and the redundancies in the mechanisms of action of ascorbate as (1) a non-specific antioxidant, (2) an inhibitor of S-nitrosylation of arginase, and (3) a chemical stabilizer/resynthesizer of BH4, we now aim to explore the role of BH4 deficiency in NOS uncoupling in aged human skin. In Specific Aim 2 we will determine the roles of BH4 and reduced substrate availability in the NOS uncoupling that results in attenuated NO-dependent reflex cutaneous VD in aged skin. In Specific Aim 3 we will test the efficacy of systemic oral BH4 supplementation strategies in improving reflex cutaneous VC and VD in aged human subjects during thermal stress (whole body cooling and heating; in separate experiments). PUBLIC HEALTH RELEVANCE: As a larger percent of the population surpasses retirement-age, the health issues of the elderly become pervasive exacting emotional, physical and financial costs. The results from this study will provide new and important information on the physiology governing impaired vasoconstriction and vasodilation in older humans that leads to thermal injury and death. Furthermore, results from these studies may provide an oral intervention strategy to functionally improve impaired cutaneous vasoreactivity in the aged during thermal stress.
描述(由申请人提供):65岁以上的人对寒冷和炎热相关的发病率和死亡率的贡献不成比例,在寒冷和炎热天气期间,所有原因导致的死亡的相对风险增加。因为即使在温和的加热或冷却过程中核心温度的偏移(即,在没有颤抖或出汗的情况下)在老年人中更大,血管调节的改变是与年龄相关的精液缺陷。最近,我们研究了年龄相关的皮肤血管收缩(VC)和血管舒张(VD)的衰减反射机制。老化皮肤中的这种减弱的反射皮肤血管反应性是由于肾上腺素能VC和活性胆碱能VD共递质的功能丧失以及下游血管信号传导的改变,包括(1)肾上腺素能脱敏和(2)一氧化氮(NO)可用性降低。这项工作的逻辑延伸,由挑衅性的初步和试点数据的支持,是检查氧化剂诱导的减少四氢生物蝶呤(BH 4)的生物利用度在老年皮肤血管系统中的作用。人类衰老与氧化应激的增加有关,导致关键酶辅因子BH 4的破坏。BH 4在整个神经和血管组织中普遍存在,并且已经成为可能是减弱反射皮肤VC和VD机制的基础的可行的分子靶标。BH 4中的维生素C相关缺陷似乎在皮肤VC反射减弱中发挥核心作用。在肾上腺素能神经末梢中,BH 4通过充当酪氨酸羟化酶的关键辅因子并通过维持酶处于其还原活性形式来合成和包装儿茶酚胺。在具体目标1中,我们将在单独的实验中使用生理学和药理学刺激来诱导交感神经VC,以研究降低的BH 4生物利用度在老年皮肤中的衰减反射VC中的作用。BH 4也是一个必要的辅因子为NO-合酶(NOS)亚型,这是必要的反射皮肤VD的充分表达。NOS在底物和/或氧化剂诱导的BH 4缺乏期间解偶联,导致超氧化物产生。增加NOS的底物利用率和/或提供超生理剂量的抗坏血酸盐增强了老年人皮肤中NO依赖性VD。由于底物可用性在NOS解偶联中的假定作用,以及抗坏血酸作为(1)非特异性抗氧化剂,(2)抗坏血酸酶的S-亚硝基化抑制剂和(3)BH 4的化学稳定剂/再合成剂的作用机制中的冗余,我们现在的目标是探索BH 4缺乏在老年人皮肤中NOS解偶联中的作用。在具体目标2中,我们将确定BH 4和降低的底物可用性在NOS解偶联中的作用,该解偶联导致老化皮肤中NO依赖性反射皮肤VD减弱。在具体目标3中,我们将测试全身口服BH 4补充策略在热应激(全身冷却和加热;在单独的实验中)期间改善老年人受试者的反射皮肤VC和VD的功效。公共卫生相关性:随着越来越多的人口超过退休年龄,老年人的健康问题变得普遍,需要付出情感、身体和经济代价。这项研究的结果将提供新的和重要的信息,在老年人的血管收缩和血管舒张受损,导致热损伤和死亡的生理学。此外,这些研究的结果可能提供一种口服干预策略,以在功能上改善老年人在热应激期间受损的皮肤血管反应性。

项目成果

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W. LARRY KENNEY其他文献

W. LARRY KENNEY的其他文献

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{{ truncateString('W. LARRY KENNEY', 18)}}的其他基金

Identification of Critical Thermal Environments for Aged Adults
老年人关键热环境的识别
  • 批准号:
    10161701
  • 财政年份:
    2020
  • 资助金额:
    $ 37.92万
  • 项目类别:
Identification of Critical Thermal Environments for Aged Adults
老年人关键热环境的识别
  • 批准号:
    10364699
  • 财政年份:
    2020
  • 资助金额:
    $ 37.92万
  • 项目类别:
Identification of Critical Thermal Environments for Aged Adults
老年人关键热环境的识别
  • 批准号:
    10579937
  • 财政年份:
    2020
  • 资助金额:
    $ 37.92万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    8099649
  • 财政年份:
    2007
  • 资助金额:
    $ 37.92万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    7872958
  • 财政年份:
    2007
  • 资助金额:
    $ 37.92万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    7494137
  • 财政年份:
    2007
  • 资助金额:
    $ 37.92万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    7296598
  • 财政年份:
    2007
  • 资助金额:
    $ 37.92万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    7642495
  • 财政年份:
    2007
  • 资助金额:
    $ 37.92万
  • 项目类别:
EFFECT OF HYDRATION STATUS ON BASKETBALL PERFORMANCE: 12-15 YEAR-OLD BOYS
水分状态对篮球表现的影响:12-15 岁男孩
  • 批准号:
    7378538
  • 财政年份:
    2006
  • 资助金额:
    $ 37.92万
  • 项目类别:
EFFECT OF HYDRATION STATUS ON BASKETBALL PERFORMANCE: 16-30 YEAR-OLD MEN
水分状态对篮球表现的影响:16-30 岁男性
  • 批准号:
    7378533
  • 财政年份:
    2006
  • 资助金额:
    $ 37.92万
  • 项目类别:

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肾上腺素能药物治疗AD疗效的临床前试验
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