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

• 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
• 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

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.

热休克蛋白70在糖尿病血管功能障碍中的双重作用 R15 -申请人Kenia Nunes 项目总结/摘要 血管损伤是一个重要的健康问题，与高血糖症有关，高血糖症是糖尿病的关键组成部分。 两种类型的糖尿病。这项研究的基本原理是， 与高水平的循环热休克蛋白70（HSP 70）有关，HSP 70是一种有趣的分子， 在不同细胞区室中共存并发挥拮抗作用的分子伴侣。有 一个众所周知的热休克蛋白70和钙离子之间的串扰，但不是在平滑肌。最近，我 实验室表明，在低血压条件下， 生理条件，因为它影响Ca 2+处理机制。在糖尿病中， eHSP 70水平增加，这与氧化应激和低级别 炎症因此，有理由认为，HSP 70可以决定血管性疾病的结局。 这种疾病的伤害。尽管如此，iHSP 70是否影响血管Ca 2+信号传导仍是未知的。 如果eHSP 70有助于血管功能和结构 糖尿病的改变该项目的中心假设，根据文献制定 我的初步数据显示，HSP 70在糖尿病诱导的血管生成中起着双重作用， 功能障碍这项研究是创新的，因为它将独立调查的相互作用 iHSP 70和Ca 2+处理机制之间的关系导致功能和结构变化 在2型糖尿病小鼠模型中选择性靶向eHSP 70 来阻止这些变化。我将联合收割机结合一套成熟的体外、离体和体内 方法，通过使用最先进的技术，如原子力显微镜和 超声检查（脉搏波速度），以允许在宏观，微观和纳米尺度的观察。 此外，性别在决定组织产生HSP 70的速率方面起着至关重要的作用;因此，我们 将使用雄性和雌性动物。在这项研究中概述的实验将解决每一个具体的 利用我实验室的优势有效地瞄准目标。此外，生物学和 工程将建立与生物医学工程的资深教授合作。 PI在该领域拥有丰富的经验，并将密切监督学生。成果 这项研究有巨大的潜力，发现目标机制，以管理糖尿病 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。