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个安全的体内人体模型，可以转化雷帕霉素（Rapa）在小鼠中扩大寿命的矛盾启示，但会引起内皮功能障碍。我们的试点项目将通过使用局部，非侵入性和微创技术来开发这种新模型，以检查局部RAPA治疗在人体小区域中的影响，从而消除了全身药物管理的风险。 尽管有抗衰老作用，但据报道，RAPA通过增加的氧化和硝化应激会导致内皮功能障碍，这是一种有害过程，导致动脉粥样硬化和其他人类血管疾病。临床研究发现，Rapa洗脱支架会诱导内皮功能障碍，并增加人类的内部血栓形成风险。 因此，Rapa似乎具有长期追求的抗衰老作用，但可能具有有害的心血管效应。如果要安全地将RAPA安全地转化为临床医学作为一种抗衰老疗法，则必须解释这种令人困惑的影响二分法。尽管Rapa似乎具有抗衰老的好处，但我们假设有害的血管内皮效应限制了其在人类中的有用性。我们将在开发和验证我们的本地治疗模型时要解决的具体目标是定义：i。在局部应用的软膏中，RAPA的最佳浓度可重现且功能相关的MTOR抑制（21，51）。 II.在皮肤中，局部抑制作用，用RAPA软膏治疗MTOR抑制，皮肤中的核氧化氢，过氧化氢，生物利用度NO，NADPH氧化酶和内皮NOS水平都会改变（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抑制是否会改变内皮功能（28、32、47）。 目标将在健康的人类受试者中解决。 Rapa软膏将用于治疗一种前臂的皮肤，并且软膏车将用于治疗对侧前臂；因此，每个主题都是他/她自己的控制。在RAPA处理的和车辆处理的皮肤区域之间，将比较RAPA输送，超氧化物和H2O2水平，生物利用度NO以及对局部皮肤变暖的内皮反应的测量。我们提出的模型将使我们能够安全地确定RAPA对体内人类血管功能的影响；将Rapa转化为人类抗衰老疗法的基本先决条件。