Age and Control of Human Skin Flow

人类皮肤流动的年龄和控制

• 批准号: 8129586
• 负责人: W. LARRY KENNEY
• 金额: $ 37.68万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8129586
• 关键词: Acute; Adrenergic Agents; Adrenergic Receptor; Age; Aging; Antioxidants; Attenuated; Biological Availability; Blood Vessels; Catecholamines; Cessation of life; Chemicals; Chronic; Cutaneous; Data; Dose; Elderly; Emotional; Enzymes; Financial cost; Funding; Health; Heating; Human; Infusion procedures; Intervention; Mediating; Microdialysis; Molecular Target; Morbidity - disease rate; Nerve; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Oral; Oxidants; Oxygen; Physiological; Physiology; Play; Population; Production; Protein Isoforms; Reflex action; Regulation; Relative Risks; Retirement; Role; Seminal; Shivering; Signal Transduction; Skin; Skin Aging; Skin Tissue; Stimulus; Superoxides; Supplementation; Sweat; Sweating; Temperature; Testing; Tissues; Tyramine; Tyrosine; Tyrosine 3-Monooxygenase; Vasodilation; Vasomotor; Weather; Woman; Work; adrenergic; age related; aged; arginase; ascorbate; cholinergic; cofactor; desensitization; efficacy testing; functional loss; heat injury; human subject; improved; inhibitor/antagonist; men; mortality; oxidant stress; receptor sensitivity; relating to nervous system; research study; response; tetrahydrobiopterin; thermal stress; vasoconstriction; Acute; Adrenergic Agents; Adrenergic Receptor; Age; Aging; Antioxidants; Attenuated; Biological Availability; Blood Vessels; Catecholamines; Cessation of life; Chemicals; Chronic; Cutaneous; Data; Dose; Elderly; Emotional; Enzymes; Financial cost; Funding; Health; Heating; Human; Infusion procedures; Intervention; Mediating; Microdialysis; Molecular Target; Morbidity - disease rate; Nerve; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Oral; Oxidants; Oxygen; Physiological; Physiology; Play; Population; Production; Protein Isoforms; Reflex action; Regulation; Relative Risks; Retirement; Role; Seminal; Shivering; Signal Transduction; Skin; Skin Aging; Skin Tissue; Stimulus; Superoxides; Supplementation; Sweat; Sweating; Temperature; Testing; Tissues; Tyramine; Tyrosine; Tyrosine 3-Monooxygenase; Vasodilation; Vasomotor; Weather; Woman; Work; adrenergic; age related; aged; arginase; ascorbate; cholinergic; cofactor; desensitization; efficacy testing; functional loss; heat injury; human subject; improved; inhibitor/antagonist; men; mortality; oxidant stress; receptor sensitivity; relating to nervous system; research study; response; tetrahydrobiopterin; thermal stress; vasoconstriction

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岁以上的人类对寒冷和热量相关的病态和死亡率和死亡的相对风险不成比例，在寒冷和炎热的天气中，各种原因的相对死亡风险增加。因为在老年人中，甚至在轻度加热或冷却期间的核心温度偏移（即，在没有发抖或出汗的情况下）更大，因此血管舒张舒适的调节是与精确年龄相关的缺陷。最近，我们研究了与年龄相关的减弱反射皮肤血管收缩（VC）和血管舒张（VD）的机制。这种衰老的皮肤中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共晶剂的功能丧失以及下游血管信号传导的改变，包括（1）肾上腺脱敏性，以及（2）降低一氧化氧化物（NO）的可用性。该工作的逻辑扩展在挑衅性的初步和初步数据的支持下，检查氧化剂诱导的降低的四氢无生物蛋白（BH4）生物利用度在老化的皮肤脉管系统中的作用。人衰老与氧化应激的增加有关，从而导致关键酶辅因子BH4的破坏。 BH4在整个神经组织和血管组织中无处不在，并且已成为可行的分子靶标，可能是损害反射皮肤VC和VD机制的基础。 BH4中与年龄相关的缺陷似乎在减弱的反射皮肤VC中起着核心作用。在肾上腺素能神经末端，通过作为酪氨酸羟化酶的关键辅助因子并通过将酶保持在其还原的活性形式中，BH4是对儿茶酚胺的合成和包装所必需的。在特定的目标1中，我们将在单独的实验中使用生理和药理刺激来研究降低BH4生物利用度在老年皮肤中的衰减反射VC中的作用，以诱导交感神经VC。 BH4也是无合酶（NOS）同工型的必需辅助因子，这对于全面表达了反射皮肤VD所必需。在底物和/或氧化剂诱导的BH4缺陷期间的NOS未成年导致超氧化物产生。提高NOS的底物可用性和/或提供抗坏血酸的超生理剂量增加了老年人皮肤中无依赖性VD。 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人皮。在特定的目标2中，我们将确定BH4的作用和降低的底物在NOS解耦合中的作用，从而导致老年皮肤中无依赖性反射皮肤VD减弱。在特定目标3中，我们将测试全身口服BH4补充策略在热应力（全身冷却和加热;在单独的实验中）在老年人受试者中改善反射皮肤VC和VD的功效。公共卫生相关性：随着人口的较大百分比超过退休年龄，老年人的健康问题成为普遍的情感，身体和财务成本。这项研究的结果将提供有关导致热损伤和死亡的老年人血管收缩和血管舒张受损的生理学的新重要信息。此外，这些研究的结果可能会提供口服干预策略，以在热应力期间在功能上提高年龄的皮肤血管反应性受损。