Role of Autophagy in Type 2 Diabetes Microvascular Dysfunction

自噬在 2 型糖尿病微血管功能障碍中的作用

• 批准号: 10523896
• 负责人: William E Hughes
• 金额: $ 10.76万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523896
• 关键词: Address; Adult; Agonist; Animal Model; Arteries; Autophagocytosis; Basic Science; Biogenesis; Blood Vessels; Cardiomyopathies; Cardiovascular system; Chloroquine; Clinical; Clinical Sciences; Clinical Trials; Collaborations; Complement; Coupled; Cutaneous; Data; Defect; Development Plans; Diabetes Mellitus; Dilator; Disease; Disease Progression; Endothelium; Ensure; Environment; Event; Exposure to; Faculty; Functional disorder; Future; Genetic; Glucose; Goals; Health; Human; Human Subject Research; Hydrogen Peroxide; Hyperemia; Hyperglycemia; Impairment; Investigation; Knowledge; Laboratories; Laser-Doppler Flowmetry; Lasers; Lysosomes; Maintenance; Mediating; Mediator of activation protein; Mentors; Mentorship; Microcirculation; Microdialysis; Microvascular Dysfunction; Mitochondria; Molecular; Nature; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oxidation-Reduction; Oxidative Stress; Pathologic; Pharmacology; Phase; Physiological; Physiology; Positioning Attribute; Production; Reactive Oxygen Species; Repression; Research; Research Personnel; Resistance; Retinal Diseases; Risk Factors; Role; Science; Scientist; Senior Scientist; Series; Technical Expertise; Techniques; Training; Translating; Trehalose; Vascular Diseases; Vasodilation; Viral; arteriole; cardiovascular disorder risk; cardiovascular risk factor; career; career development; endothelial dysfunction; experience; gene repression; in vivo; inhibition of autophagy; microvascular pathology; mortality; multidisciplinary; novel; overexpression; post-doctoral training; preservation; programs; response; sabbatical; shear stress; skills; transcription factor; translational model; translational study

Project Summary This K99/R00 application proposes a comprehensive career development plan and a series of investigations, coupled with an outstanding mentoring committee specifically tailored to assist completion of postdoctoral training and establish an independent research program. This proposal is multi-faceted, leveraging previous training in human subjects research to complement current postdoctoral training to investigate the fundamental mechanisms underlying microvascular dysfunction in Type 2 Diabetes Mellitus (T2DM). Autophagic flux is necessary to maintain a healthy microvascular environment. T2DM is associated with reductions in autophagic flux, however whether this underlies the rampant microvascular defects associated with the disease is unclear. During the K99 phase we will examine whether T2DM is associated with a pathological switch in the mechanism of microvascular vasodilation to shear stress in isolated arterioles, and examine whether autophagic flux contributes to cutaneous microvascular function in T2DM using laser Doppler flux coupled with microdialysis. Dr. Hughes will train under the mentorship of a transdisciplinary group of senior scientists with research expertise in mechanisms of microvascular dysfunction, and examination of cutaneous microvascular function within the context of T2DM. The current postdoctoral mentors, Drs. David Gutterman and Andreas Beyer, both of whom have extensive experience mentoring trainees will continue to serve as mentors. They will be complemented by mentoring expertise from Naomi Hamburg and Lacy Alexander. The primary goal is to become an expert in the field of human microvascular physiology within the context of T2DM. This will be achieved through 1) expansion of technical skills including molecular techniques, along with laser Doppler flowmetry coupled with microdialysis; and 2) empirical training in lab and clinical trial management, along with team science and mentoring skills. Achieving these goals will strengthen further scholarly activities, establish important collaborations, and acquire critical data that will ensure a successful transition to independence. The training plan will be strengthened through a sabbatical in the laboratory of Dr. Lacy Alexander, where Dr. Hughes will be trained in investigation of microvascular function in the human cutaneous microvasculature. Obtaining an independent educational experience in one of the world’s most successful laboratories that utilize this technique will strengthen the ability to conduct translational studies. Collectively, this team will provide an outstanding training environment that will fill critical gaps in knowledge and skill set relating to the mechanisms contributing to microvascular dysfunction in T2DM. For the transition to independence phase, the mechanistic contribution of Transcription Factor EB (TFEB), a master regulator of lysosome biogenesis, will be investigated utilizing the skills and techniques learned and mastered during the K99 phase. The components of this application are consistent with the career goals of becoming an independent investigator whose research intersects basic and clinical science.

项目概要 此次K99/R00申请提出了全面的职业发展计划和一系列的调查， 加上专门为协助完成博士后而设计的杰出指导委员会 培训并建立独立的研究计划。该提案是多方面的，利用了以前的建议 人类学科研究培训，以补充当前的博士后培训，以调查基本原理 2 型糖尿病 (T2DM) 微血管功能障碍的潜在机制。自噬通量为 维持健康的微血管环境所必需的。 T2DM 与自噬减少有关 然而，这是否是与该疾病相关的猖獗微血管缺陷的基础尚不清楚。 在K99阶段，我们将检查T2DM是否与机制中的病理转换相关 微血管舒张对孤立小动脉剪切应力的影响，并检查自噬通量是否 使用激光多普勒通量与微透析相结合，有助于 T2DM 患者的皮肤微血管功能。博士。 休斯将在一个由具有研究专业知识的跨学科资深科学家小组的指导下进行培训 微血管功能障碍的机制，以及皮肤微血管功能的检查 T2DM 的背景。现任博士后导师Drs.大卫·古特曼和安德烈亚斯·拜尔，两人 拥有丰富辅导经验的学员将继续担任导师。他们将得到补充 内奥米·汉堡和莱西·亚历山大的专业指导。主要目标是成为该领域的专家 T2DM 背景下的人类微血管生理学领域。这将通过 1) 扩展来实现 技术技能，包括分子技术、激光多普勒血流测定法和微透析； 2) 实验室和临床试验管理方面的实证培训，以及团队科学和指导技能。 实现这些目标将加强进一步的学术活动，建立重要的合作，并获得 将确保成功过渡到独立的关键数据。培训计划将加强 通过在莱西·亚历山大博士的实验室休假，休斯博士将在那里接受调查的培训 人体皮肤微血管的微血管功能。获得独立的教育 在世界上最成功的实验室之一利用该技术的经验将增强能力 进行转化研究。总的来说，该团队将提供出色的培训环境， 填补与微血管功能障碍机制相关的知识和技能方面的关键空白 在 T2DM 中。对于向独立阶段的过渡，转录因子 EB 的机制贡献 （TFEB）是溶酶体生物发生的主要调节者，将利用所学到的技能和技术进行研究 并在K99阶段掌握。该应用程序的组成部分与职业目标一致 成为一名独立研究者，其研究涉及基础科学和临床科学。