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Chronic Systemic Inflammation: Functional organ cross-talk in inflammatory disease and cancer

Periodic Reporting for period 2 - CSI-Fun (Chronic Systemic Inflammation: Functional organ cross-talk in inflammatory disease and cancer)

Reporting period: 2019-12-01 to 2021-05-31

The main goal of this project is to gain a better understanding of Chronic Systemic Inflammation (CSI), which is likely responsible for the progression of several common diseases, such as Psoriasis, Arthritis and Cancer. To achieve this goal, we focus on whole body physiology in relation to systemic inflammation as a cause or/and consequence of these common human diseases. There is no good understanding of the molecular mechanisms underlying these diseases, which represent serious health issues worldwide. It is therefore important to conduct well-controlled experiments in several model systems, from the petri dish to samples donated by patients, to find new and powerful ways (biomarkers) to detect each disease early, when it has the highest chances to be treatable, as well as new methods to treat, and even better to prevent its occurrence.
Our work focus on three important common diseases:
1. Inflammatory Skin Diseases (ISD): such as Atopic Dermatitis (AD) and Psoriasis. These are frequently occurring, chronic skin conditions that can lead to a significant deterioration of life quality: 5–30% of children and 2–10% of adults develop AD and Psoriasis affects 3-5% of the population. These two diseases are caused by perturbations in the interactions between the immune system and the most important cell type of the skin epidermis, the keratinocytes. The objective of our project is to carefully study how the immune system and the skin interact during the course of these diseases, to understand what goes wrong and why, to find possible biomarkers and treatment targets and -when possible- to test the validity of the biomarkers or treatments we would discover in model systems and/or in patient samples.
2. Inflammatory Joint Diseases (IJD): such as Psoriatic Arthritis (PsA), which affects up to 30% of psoriatic patients and leads to joint pain, stiffness and swelling. Debilitating joint degeneration also occurs in Osteoarthritis (OA), the most common joint disease that affects millions of people. OA has often been referred to as a "wear and tear" disease, where the cartilage is slowly eroded, but it is now recognized that OA affects the entire joint including a role of inflammation. The objective of our project is to carefully study how perturbations in epidermis-immune system interactions lead to distant effects on the joints in PsA and how inflammation/immune system perturbations can affect joint degeneration in OA. In addition, we plan to carefully compare the two types of joint diseases to find commonalities and differences. The final goal is again to find biomarkers and therapeutic targets.
3. Cancer associated Cachexia (CAC): Cancer-associated cachexia is a disorder of the whole body that affects 50-80% of cancer patients. CAC is characterized by involuntary loss of body weight due to specific wasting of muscles and fat tissues. CAC is extremely detrimental to cancer patients’ quality of life and is considered the immediate cause of death for 22-40% of cancer patients. It is therefore very important to find biomarkers that can help predicting as early as possible, which cancer patient is likely to develop cachexia to adapt treatment and lifestyle and prevent or delay cachexia as much as possible.
What causes Cancer cachexia is poorly understood but uncontrolled inflammation, perturbed hormone balance and the nervous system appear to be important. The objective of our project is to study how these three main suspects operate and –most importantly- interact in CAC using model systems that closely resemble the cancer patient situation. Our main objective is to identify biomarkers that could be tested at the moment of cancer diagnosis and therefore benefit CAC prevention.
Within the 30 first months of the project, the 1st year (12 months) was devoted to establish the new laboratory at the Medical University of Vienna (MUW), Austria, whereas the past 10 months were affected by the COVID restrictions, which did not allow us to interview and hire people and forced us to work in the laboratory at a modest capacity. Despite these delays and problems, we performed well and obtained robust results, some of which are now published in international peer-reviewed scientific journals. Work published in these articles unravel new molecules that are good candidate biomarkers in Psoriasis, AD and Bone Cancer.
For detailed information on the three most important articles published in this project up to now, see the links to two institutional press releases issued by the Medical University of Vienna:

https://www.meduniwien.ac.at/web/en/about-us/news/detailsite/2019/news-im-november-2019/genetic-alterations-in-skin-stem-cells-can-trigger-psoriasis/
https://www.meduniwien.ac.at/web/en/about-us/news/detailsite/2020/news-im-juli-2020/novel-therapeutic-approaches-for-aggressive-bone-cancer/

We are continuing our work along the 3 objectives despite the current limitations and are building up on our results with new/follow up experiments to make important discoveries and ascertain the robustness and usefulness of our findings.
We expect to discover more biomarkers and to be able to propose new treatment regimens and new therapeutic targets for Psoriasis, PsA, OA, Cancer and CAC.
Picrosirius red staining of mouse Osteosarcoma under optical/polarized light to visualize collagens