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在糖尿病诱导的血管功能障碍中的双重作用