Project Details
Projekt
The Neuro-Immune Axis linking Psychosocial Stress with Atherosclerosis
Applicant
Dr. Alexander Leunig
Subject Area
Cardiology, Angiology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 559481340
This project will investigate the role of chronic psychosocial stress in the progression of atherosclerosis. It will explore how brain circuits are involved in regulating the peripheral immune response to stress. Despite significant advancements in our understanding of atherosclerosis, the prevalence and mortality rates of atherosclerosis and cardiovascular disease remain high. Chronic psychosocial stress has not been focused on as much as other risk factors in research on atherosclerosis despite its potential impact on disease progression. Historically marginalized groups are especially affected by chronic psychological and environmental stress, which worsens cardiovascular disease burden. Hence, more mechanistic insight is urgently needed. The project builds upon existing expertise in investigating the role of the immune-brain axis in the host laboratory and aims to uncover how chronic stress exacerbates atherosclerosis. Preliminary data from chronic social witness defeat stress (CSWDS) models suggest that stress exacerbates atherosclerosis through immune-mediated processes rather than metabolic factors like cholesterol. The central hypothesis is that the hypothalamic-pituitary-adrenal (HPA)-axis is a central pathway for the distribution and function of immune cells in atherosclerosis progression after CSWDS. Additionally, we propose that HPA-axis specific CRH+ neurons in the PVH are responsible for stress-induced aggravation of atherosclerosis via glucocorticoid receptors in leukocytes.Specifically, the project will focus on two key areas. First, it will examine how hypothalamic corticotropin-releasing hormone (CRH) neurons within the paraventricular hypothalamus modulate leukocyte recruitment to atherosclerotic plaques. This will be explored with loss-of-function manipulations of CRH neurons and following CSWDS. Second, the project will examine the role of glucocorticoid receptor signaling in leukocytes, specifically how CSWDS-induced glucocorticoid release by the HPA-axis alters immune responses and accelerates plaque formation in the presence or absence of glucocorticoid receptor on leukocytes. The project will utilize cutting-edge techniques, such as chemogenetic and pharmacological manipulation of the HPA-axis, genetic knockouts, flow cytometry, and immunohistochemistry. The anticipated results are a deeper understanding of HPA-axis driven acceleration of atherosclerosis following CSWDS. This project will help establish a mechanistic link between the HPA-axis and immune cell-mediated atherosclerosis progression during chronic stress. The project utilizes technical expertise and resources of the host laboratory and benefits from strong collaborations with cardiovascular and neuroscientific partner laboratories at Mount Sinai.
DFG Programme
WBP Fellowship
International Connection
USA
