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: 10673182
• 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/10673182
• 关键词: 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; Education; 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; Learning; Lysosomes; Maintenance; Mediating; Mediator; Mentors; Mentorship; Microcirculation; Microdialysis; Microvascular Dysfunction; Mitochondria; Molecular; Nature; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oxidation-Reduction; Oxidative Stress Induction; Pathologic; Phase; Physiological; Physiology; Positioning Attribute; Postdoctoral Fellow; 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; Vascular Endothelium; 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; pharmacologic; post-doctoral training; preservation; programs; response; sabbatical; shear stress; skills; transcription factor; translational model; translational study; vascular endothelial dysfunction

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.

项目摘要 本K99/R 00申请提出了全面的职业发展计划和一系列的调查， 再加上一个杰出的指导委员会专门为协助完成博士后 培训和建立独立的研究计划。该提案是多方面的，利用了以前的 培训人类受试者的研究，以补充目前的博士后培训，调查的基本 2型糖尿病（T2 DM）微血管功能障碍的潜在机制。自噬通量是 维持健康的微血管环境。T2 DM与自噬细胞减少相关 然而，这是否是与该疾病相关的猖獗的微血管缺陷的基础尚不清楚。 在K99阶段，我们将检查T2 DM是否与机制中的病理转换相关。 的微血管扩张的剪切应力在孤立的小动脉，并检查是否自噬流量 使用激光多普勒流量结合微透析有助于T2 DM患者的皮肤微血管功能。博士 休斯将在一个由资深科学家组成的跨学科小组的指导下进行培训，这些科学家具有以下方面的研究专长： 微血管功能障碍的机制，并检查皮肤内的微血管功能， 关于T2 DM现任博士后导师大卫·古特曼博士和安德烈亚斯·拜尔博士， 具有丰富指导经验的学员将继续担任导师。这些建议将得到以下方面的补充： 娜奥米·汉堡和莱西·亚历山大的专业指导。主要目标是成为一个专家， T2 DM背景下的人体微血管生理学领域。这将通过1）扩展 技术技能，包括分子技术，沿着激光多普勒血流仪与微透析; 和2）实验室和临床试验管理的经验培训，沿着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 确保成功过渡到独立的关键数据。培训计划将得到加强 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培训。 在人类皮肤微血管系统中的微血管功能。获得独立的教育 在世界上最成功的实验室之一利用这种技术的经验将加强能力 进行翻译研究。总的来说，这个团队将提供一个出色的培训环境， 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 2型糖尿病对于向独立阶段的过渡，转录因子EB的机制贡献 （TFEB），溶酶体生物发生的主调节器，将利用所学的技能和技术进行研究 并在K99阶段掌握。此应用程序的组成部分与以下职业目标一致： 成为一个独立的研究者，其研究交叉基础和临床科学。