Dual Role of HSP70 in Diabetes-Induced Vascular Dysfunction

热休克蛋白70在糖尿病血管功能障碍中的双重作用 R15-申请者Kenia Nunes 项目摘要/摘要 血管损伤是一个重要的健康问题，与高血糖有关，高血糖是 两种类型的糖尿病。这项研究的基本原理是按时间顺序增加血糖水平 与更高水平的循环热休克蛋白70(HSP70)有关，这是一种有趣的分子 共存于不同细胞室并发挥拮抗作用的伴侣蛋白。的确有 HSP70和钙离子之间的一种众所周知的串扰，但不是在平滑肌肉中。就在最近，我的 实验室表明，在以下情况下，需要一个功能性的iHSP70来实现足够的血管反应性 生理条件，因为它影响钙离子的处理机制。在糖尿病中，有一种 EHSP70水平升高，与氧化应激和低级别 发炎。因此，有理由认为HSP70可以决定血管病变的结局。 在这种疾病中的损害。然而，目前尚不清楚iHSP70是否会影响血管内钙信号。 高血糖状态以及eHSP70是否对血管功能和结构起作用 糖尿病的变化。这个项目的中心假设，是根据文献提出的 而我强有力的初步数据是，HSP70在糖尿病诱导的血管中起着双重作用 功能障碍。这项研究具有创新性，因为它将独立地研究相互作用 IHSP70和钙离子调控导致功能和结构变化的机制 高血糖和选择性靶向eHSP70在2型糖尿病小鼠模型中的作用 以防止这些变化。我将结合一套成熟的体外、体外和体内 方法，通过使用最先进的技术，如原子力显微镜和 超声检查(脉冲波速)允许在宏观、微观和纳米尺度上进行观察。 此外，性别在决定组织产生HSP70的速度中起着至关重要的作用；因此，我们 将使用雄性和雌性动物。这项研究中概述的实验将针对每个特定的 利用我实验室的优势，有效地瞄准目标。此外，生物和生物之间的网络 工程学将通过与生物医学工程学的一名资深教授合作建立。 PI在这一领域有丰富的经验，并将密切监督学生。结果是 这项研究有巨大的潜力来揭示治疗糖尿病的靶向机制 血管病，同时创造一个多学科的环境，提供广泛的研究培训 给本科生。我们的发现将通过开启新的研究而产生更广泛的影响 与血管结构和功能改变相关的其他疾病状态的途径。

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.