Periodic Reporting for period 2 - WATCH (Well-Aging and the Tanycytic Control of Health)
Période du rapport: 2020-09-01 au 2022-02-28
Energy homeostasis is maintained by neuroendocrine circuits – neurons and glia - located in the hypothalamus, a small and highly specialized part of the brain. These circuits can sense and integrate metabolic feedback in the form of molecules such as glucose or hormones from peripheral tissues that signal hunger or satiety, and thus adapt the response of the organism to physiological demands. Tanycytes are peculiar glial cells present in a part of the hypothalamus that is both exposed to blood-borne signals and secretes neuroendocrine signals from the brain into the circulation to control the function of peripheral tissues, thanks to the fact that the endothelial cells lining the blood vessels in this region are “fenestrated” (that is, having windows) instead of walling off the blood from the brain tissue as in most other brain regions. Among their characteristics, tanycytes act as linchpins of this two-way exchange process, forming a bridge between the blood contained in the fenestrated blood vessels and the cerebrospinal fluid contained in brain pockets known as ventricles, which connects this part of the hypothalamus with other brain regions. Tanycytes can thus ferry signals across the traditional barriers that separate the two compartments, allowing them to reach, notably, neurons that regulate food intake or other physiological processes. In addition to their shuttling properties, they are also capable of undergoing morphological and functional changes in coordination with the endothelial cells lining the fenestrated blood vessels, thereby controlling the entry or exit of signaling molecules and hormones in response to bodily needs.
The overarching goal of WATCH is to use a variety of techniques, animal models and patients with metabolic or neurodegenerative diseases to explore the role of these unique and versatile cells, and develop new therapeutic approaches based on improving or restoring their function for a variety of disorders that impair well-aging.
Given the preoccupying nature of the COVID-19 pandemic and the intriguing observation that most COVID-19 patients shown symptoms of brain infection, we have also been working on whether and how SARS-CoV-2, the virus responsible for COVID-19, enters brain cells, why certain individuals are at higher risk for severe forms of the disease, and whether we can predict or limit the long-term consequences of infection.
Several other studies are in the pipelines.
In the WATCH project, we would like to understand the process as a whole, as well as the contribution of tanycytes to the entry of metabolic signals from the blood into the brain, and how these signals are interpreted to change the activity of the neurons sensing them in order to affect the behavior or functional response of the individual. Specifically, we aim to go beyond the state of the art regarding this process first by developing new tools or adapting existing tools to allow us to distinguish between different subpopulations of these sparse cell types and to identify and block individual steps in the transport and regulatory mechanisms, and second, by studying which of these subpopulations react to a specific physiological or pathological condition, in conjunction with what other cells and in what manner.
We have developed a number of techniques that can used to separate, observe or interfere with these molecular processes in living cells or animals and made several novel observations. By the end of the project, once we have obtained a more detailed understanding of the mechanisms through which these cells perform their functions and how they are altered with aging or under disease conditions, for example due to obesity, diabetes, Alzheimer disease or other neurodegenerative disorders, we can design ways to interfere with these pathological changes or restore normal function, thus providing a road-map for well-aging.