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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要这项K99/R00应用程序提出了一项全面的职业发展计划和一系列投资，加上专门针对辅助完成博士后量身定制的杰出心理委员会培训并建立独立的研究计划。该建议是多方面的，利用了以前的人类受试者研究以完成当前的博士后培训，以调查基本 2型糖尿病（T2DM）中微血管功能障碍的机制。自噬通量是维持健康的微血管环境所必需的。 T2DM与自噬的减少有关但是，通量，这是否是与该疾病相关的猖ramp的微血管缺陷的基础。在K99阶段，我们将检查T2DM是否与机制中的病理开关有关微血管血管舒张以在分离的动脉中剪切应力，并检查自噬通量是否是否使用与微透析结合的激光多普勒通量，有助于T2DM的皮肤微血管功能。博士休斯将在具有研究专业知识的跨学科高级科学家的心态下进行训练微血管功能障碍的机制，并检查了皮肤微血管功能 T2DM的上下文。当前的博士后导师，博士。大卫·古特曼（David Gutterman）和安德烈亚斯·拜尔（Andreas Beyer）拥有丰富的心理学员将继续充当思维方式。他们将由 Naomi Hamburg和Lacy Alexander的指导专业知识。主要目标是成为专家 T2DM背景下人类微血管生理的领域。这将通过1）扩展来实现包括分子技术在内的技术技能，以及激光多普勒流量指标，以及微透析； 2）实验室和临床试验管理中的实证培训以及团队科学和心理技能。实现这些目标将加强进一步的科学活动，建立重要的合作并获得关键数据将确保成功过渡到独立性。培训计划将得到加强通过拉西·亚历山大博士的实验室的休假，休斯博士将接受调查的培训人皮肤微血管系统中的微血管功能。获得独立教育在世界上最成功的实验室之一中，利用这项技术的经验将增强能力进行翻译研究。总的来说，该团队将提供出色的培训环境填补与导致微血管功能障碍的机制有关的知识和技能集的关键空白在T2DM中。对于过渡到独立阶段的转录因子EB的机理贡献（TFEB）是溶酶体生物发生的主要调节剂，将使用所学的技能和技术研究并在K99阶段掌握。此应用程序的组成部分与成为一名独立研究者，其研究与基础科学相交。