Dual Role of HSP70 in Diabetes-Induced Vascular Dysfunction

HSP70 在糖尿病引起的血管功能障碍中的双重作用

基本信息

批准号：
10515009
负责人：
Kenia Pedrosa Nunes
金额：
$ 43.42万
依托单位：
FLORIDA INSTITUTE OF TECHNOLOGY
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：
2022-08-04 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515009
关键词：
Address Affect Agonist Animals Antibodies Aorta Atomic Force Microscopy Automobile Driving Biology Biomedical Engineering Blood Vessels Cell Adhesion Cell Compartmentation Cells Chronology Collaborations Confocal Microscopy Cultured Cells Data Deposition Diabetes Mellitus Disease Engineering Environment Enzyme-Linked Immunosorbent Assay Exposure to Extracellular Matrix Female Florida Glucose Health Heat-Shock Proteins 70 Human Hyperglycemia ITPR1 gene Immune system Immunoglobulin G In Vitro Inflammation Interleukin-1 beta Interleukin-6 Laboratories Link Literature Measures Mesentery Methods Molecular Molecular Chaperones Mus NADPH Oxidase Non-Insulin-Dependent Diabetes Mellitus Outcome Outcomes Research Oxidative Stress Pharmaceutical Preparations Pharmacology Physiologic pulse Physiological Play Proteins Research Research Training Rho-associated kinase Role Science Serum Severities Signal Transduction Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Source Students Supervision TNF gene Techniques Testing Thermogenesis Tissues Transforming Growth Factor beta Ultrasonography Up-Regulation Vascular Diseases Vascular Smooth Muscle Western Blotting arterial stiffness base cytokine db/db mouse diabetes management experience experimental study extracellular in vivo inhibitor innovation knock-down male mouse model multidisciplinary nanoscale prevent professor response sex ultrasound undergraduate student

项目摘要

Dual role of HSP70 in diabetes-induced vascular dysfunction R15 – Applicant Kenia Nunes Project Summary/Abstract Vascular damage, a significant health problem, is linked to hyperglycemia, a key component of both types of diabetes. The rationale for this study is that increased glucose levels chronologically associate with higher levels of circulating Heat-shock protein 70 (HSP70), an intriguing molecular chaperone that co-exists in different cell compartments and exerts antagonistic actions. There is a well-known crosstalk between HSP70 and Ca2+, but not in smooth muscle. Only recently, my lab showed that a functional iHSP70 is required for adequate vascular reactivity under physiological conditions, as it impacts Ca2+ handling mechanisms. In diabetes, there is an increase in the levels of eHSP70, which is associated with oxidative stress and low-grade inflammation. Thus, it is reasonable to argue that HSP70 could determine the outcome of vascular damage in this disease. Still, it is unknown if iHSP70 affects vascular Ca2+ signaling under hyperglycemic conditions and if eHSP70 contributes to vascular functional and structural alterations in diabetes. The central hypothesis of this project, formulated based on the literature and my robust preliminary data, is that HSP70 plays a dual role in diabetes-induced vascular dysfunction. This study is innovative because it will independently investigate the interplay between iHSP70 and Ca2+ handling mechanisms leading to functional and structural changes under hyperglycemia and by selectively targeting eHSP70 in a murine model of type 2 diabetes to prevent these changes. I will combine a set of well-established in vitro, ex vivo, and in vivo approaches, by using state-of-art techniques such as atomic force microcopy and ultrasonography (Pulse Wave Velocity) to allow observations at macro, micro and nano scale. Also, sex plays a crucial role in determining the tissue rate of production of HSP70; therefore, we will use male and female animals. The experiments outlined in this study will address each specific aim efficiently by utilizing the strengths of my laboratory. Moreover, network between biology and engineering will be stablished by collaboration with a senior professor in Biomedical Engineering. The PI has extensive experience in the field and will closely supervise the students. The outcome of this research has an enormous potential to uncover target mechanisms to manage diabetic vasculopathies while creating a multidisciplinary environment offering extensive research training to undergraduate students. Our findings will have a broader impact by opening new research avenues for other diseased states associated with vascular structural and functional changes.

HSP70 在糖尿病引起的血管功能障碍中的双重作用 R15 – 申请人肯尼亚努内斯项目概要/摘要血管损伤是一个严重的健康问题，与高血糖有关，而高血糖是糖尿病的一个关键组成部分。这项研究的基本原理是，这两种类型的糖尿病都会按时间顺序增加血糖水平。与较高水平的循环热休克蛋白 70 (HSP70) 相关，这是一种有趣的分子共存于不同细胞区室并发挥拮抗作用的分子伴侣。 HSP70 和 Ca2+ 之间的众所周知的串扰，但直到最近才出现在平滑肌中。实验室表明，功能性 iHSP70 是在条件下足够的血管反应性所必需的生理条件，因为它影响 Ca2+ 处理机制。在糖尿病中，有一个。 eHSP70 水平增加，这与氧化应激和低级别相关因此，有理由认为 HSP70 可以决定血管的结果。然而，目前尚不清楚 iHSP70 是否会影响血管 Ca2+ 信号转导。高血糖状况以及 eHSP70 是否有助于血管功能和结构该项目的中心假设是根据文献制定的。我强有力的初步数据是，HSP70 在糖尿病诱发的血管生成中发挥双重作用这项研究具有创新性，因为它将独立研究相互作用。 iHSP70 和 Ca2+ 处理机制之间导致功能和结构变化在高血糖下并通过在 2 型糖尿病小鼠模型中选择性靶向 eHSP70 为了防止这些变化，我将结合一套成熟的体外、离体和体内方法。方法，通过使用最先进的技术，如原子力显微镜和超声波检查（脉冲波速度）可在宏观、微观和纳米尺度上进行观察。此外，性别在决定 HSP70 的组织生成率方面起着至关重要的作用，因此，我们本研究中概述的实验将使用雄性和雌性动物。利用我的实验室的优势以及生物学和生物学之间的网络来有效地实现目标。通过与生物医学工程高级教授的合作，工程将得到稳定。 PI在该领域拥有丰富的经验，并将密切监督学生的成果。这项研究具有揭示治疗糖尿病的目标机制的巨大潜力血管疾病，同时创建提供广泛研究培训的多学科环境通过开展新的研究，我们的发现将产生更广泛的影响。与血管结构和功能变化相关的其他疾病状态的途径。