Translational Model Development: Rapamycin, Aging, and Endothelial Dysfunction

转化模型开发：雷帕霉素、衰老和内皮功能障碍

• 批准号: 8515283
• 负责人: DEAN L KELLOGG
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515283
• 关键词: Address; Adult; Affect; Aging; Animal Model; Area; Atherosclerosis; Attenuated; Bioavailable; Biopsy; Blood; Blood Vessels; Cardiovascular system; Cell Aging; Cell Line; Cells; Cessation of life; Clinical Medicine; Clinical Research; Conflict (Psychology); Contralateral; Cutaneous; Data; Drug Kinetics; Endothelial Cells; FDA approved; Forearm; Functional disorder; Future; Gender; Goals; Human; Hydrogen Peroxide; Immunosuppressive Agents; Intervention; Longevity; Malignant Neoplasms; Mammals; Measurement; Messenger RNA; Microdialysis; Modeling; Monitor; Mus; NADPH Oxidase; Ointments; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological; Pilot Projects; Play; Process; Protein Subunits; Publishing; Reporting; Ribosomal Protein S6; Risk; Role; Safety; Sirolimus; Site; Skin; Skin Cancer; Stem cells; Stents; Stress; Superoxides; System; Techniques; Testing; Thromboplastin; Thrombosis; Time; Topical application; Translating; Translations; Vascular Diseases; Vascular Endothelium; Work; age effect; age related; anti aging; atherogenesis; base; bench to bedside; experience; human NOS3 protein; human subject; in vivo; innovation; interstitial; mTOR protein; male; middle age; minimally invasive; model development; neoplastic; nitrosative stress; novel strategies; prevent; programs; research study; response; restenosis; senescence; translational study

DESCRIPTION (provided by applicant): Our goal is develop a safe, in vivo human model that can translate the conflicting revelations that rapamycin (RAPA) expands lifespan in mice but yet causes endothelial dysfunction. Our pilot project will develop this new model by using local, non- invasive and minimally invasive techniques to examine the effects of local RAPA treatment in small areas of the body, obviating risks of systemic drug administration. Despite anti-aging effects, RAPA has been reported to cause endothelial dysfunction through increased oxidative and nitrosative stress, a deleterious process that leads to atherosclerosis and other human vasculopathies. Clinical studies find that RAPA eluting stents induce endothelial dysfunction and increase in-stent thrombosis risk in humans. RAPA thus appears to have long-sought anti-aging effects, but yet may have deleterious cardiovascular effects. This confusing dichotomy of effects must be explained if RAPA is to be translated safely into clinical medicine as an anti-aging therapy. Although RAPA appears to have anti-aging benefits, we hypothesize that deleterious vascular endothelium effects limits its usefulness in humans. Specific aims we will address in developing and validating our local treatment model are to define: I.the optimal concentration of RAPA in a topically applied ointment that achieves a reproducible and functionally relevant inhibition of mTOR (21, 51). II.whether interstitial superoxide, hydrogen peroxide, bioavailable NO, NADPH oxidase, and endothelial NOS levels in skin are altered by mTOR inhibition with topical treatment with RAPA ointment (13, 15, 40). III.whether mTOR inhibition by RAPA alters endothelial function by monitoring the effects of topical RAPA ointment on vascular responses to local skin warming (28, 32, 47). Aims will be addressed in healthy human subjects. RAPA ointment will be used to treat skin of one forearm and ointment vehicle will be used to treat the contralateral forearm; thus each subject will be his/her own control. Measurements of RAPA delivery, levels of superoxide and H2O2, bioavailable NO, and endothelial responses to local skin warming will be compared between RAPA-treated and vehicle-treated skin regions to address our aims. Our proposed model will allow us to safely determine the effects of RAPA on vascular function in humans in vivo; an essential prerequisite for translating RAPA into an anti-aging therapy for humans.

描述（由申请人提供）：我们的目标是开发一种安全的体内人体模型，该模型可以转化雷帕霉素（RAPA）延长小鼠寿命但引起内皮功能障碍这一相互矛盾的发现。我们的试点项目将开发这种新模型，通过使用局部、无创和微创技术来检查局部 RAPA 治疗在身体小区域的效果，消除全身给药的风险。 尽管具有抗衰老作用，但据报道 RAPA 会通过增加氧化和亚硝化应激而导致内皮功能障碍，这是一种导致动脉粥样硬化和其他人类血管疾病的有害过程。临床研究发现 RAPA 洗脱支架会诱发内皮功能障碍并增加人类支架内血栓形成的风险。 因此，RAPA 似乎具有人们期待已久的抗衰老作用，但也可能对心血管产生有害影响。如果 RAPA 要作为抗衰老疗法安全地转化为临床医学，就必须解释这种令人困惑的效果二分法。尽管 RAPA 似乎具有抗衰老功效，但我们假设有害的血管内皮效应限制了它在人类中的用途。我们在开发和验证局部治疗模型时将要解决的具体目标是定义： I. 局部应用软膏中 RAPA 的最佳浓度，以实现 mTOR 的可重复且功能相关的抑制 (21, 51)。 II. RAPA 软膏局部治疗的 mTOR 抑制是否会改变皮肤中间质超氧化物、过氧化氢、生物可利用的 NO、NADPH 氧化酶和内皮 NOS 水平 (13,15,40)。 III.通过监测局部 RAPA 软膏对局部皮肤变暖的血管反应的影响，RAPA 抑制 mTOR 是否会改变内皮功能 (28,32,47)。 目标将在健康人类受试者中实现。 RAPA软膏将用于治疗一侧前臂的皮肤，软膏载体将用于治疗对侧前臂；因此，每个受试者都将由他/她自己控制。将比较 RAPA 处理和媒介物处理的皮肤区域之间的 RAPA 递送、超氧化物和 H2O2 水平、生物可利用的 NO 以及内皮细胞对局部皮肤变暖的反应的测量结果，以实现我们的目标。我们提出的模型将使我们能够安全地确定 RAPA 对人体血管功能的影响；将 RAPA 转化为人类抗衰老疗法的重要先决条件。