Urban Lendahl

CADASIL is the most common monogenic form of cerebral small vessel disease (SVD), a group of diseases affecting more than 5.000 individuals per year in Sweden. CADASIL is caused by mutations in the NOTCH3 gene and CADASIL patients experience arteriopathy and ischemic infarcts, ultimately leading to cognitive impairment and premature death. There are currently no therapies for CADASIL, and we will therefore explore two novel therapy strategies in a CADASIL mouse model: immunization and neuroinflammation/STING blockade. To monitor disease progression in CADASIL patients, better biomarkers are warranted. We will identify potential biomarkers from a large-scale transcriptomic dataset from a CADASIL mouse model, evaluate candidate biomarkers in human and mouse histological material and assess their efficacy in blood samples from CADASIL patients, with a particular focus on neuroinflammation. Finally,  non-CADASIL disease-causing NOTCH3 mutations are emerging, and we will search for such mutations in a small cohort of “atypical” SVD and migraine patients and establish how non-CADASIL NOTCH3 mutations affect Notch signalling. Information about non-CADASIL NOTCH3 mutations is important for future therapy considerations. In sum, through a multipronged approach spanning from preclinical transcriptomic and mouse model analysis to biomarker analysis in CADASIL patients, we expect to make progress beyond the state-of-the-art in CADASIL therapy and monitoring of disease progress.

In response to the HORIZON-INFRA-2023-DEV-01-03 call, INFRAPLUS aims to expand INFRAFRONTIER's capacity for human disease modelling, refine its service portfolio by reducing animal usage and developing alternative cellular models, and optimise the use of resources. INFRAPLUS seeks to achieve several objectives: Developing national node capacities and expertise for providing innovative in vivo, in vitro and preclinical services, developing novel model systems and services to meet the demands of existing and novel user communities, and reducing environmental impact. To achieve these objectives, INFRAPLUS will focus on launching pilot services, refining new technologies, emphasising alternate cellular models, designing and implementing special training programmes and optimising resources for the entire consortium. The project includes a defined service development strategy supported by a strong IT and data management backbone and is built upon the needs of the scientific community. Ultimately, INFRAPLUS will enhance and evolve INFRAFRONTIER's capacity for modelling human diseases and enable breakthrough research by providing researchers cutting-edge tools and services to respond to global biomedical challenges.

Breast cancer, with 7,000 new patients annually, despite improved treatment, continues to pose a major medical problem, and there are many aspects of breast cancer that we do not yet understand. In recent years, it has become increasingly apparent that an important signaling mechanism called Notch signaling is often misregulated in breast cancer. This is evident, among other things, through a connection between high Notch signaling and poor prognosis for the patient. Notch signaling is important for most of the body's organs and tissues that develop normally, but when it is mutated or expressed at too high a level, this can lead to cancer. Increased Notch signaling is linked to breast cancer, and we want to understand the role this plays in several important stages of the tumor process. In this application, we want to find out how Notch in animal models can initiate breast cancer, and what other genes are involved in this. We also want to understand how Notch affects the interaction between tumor and surrounding stroma tissue. Finally, we also want to learn more about how Notch signaling interacts with other important signaling pathways in the tumor cells, inter alia with the mechanism that handles situations with low oxygen pressure in the tissue, which often occurs in tumors. The overall and long-term aim of the project is to be able to contribute to developing new and improved therapies for breast cancer. It is becoming increasingly clear that misregulated Notch signaling contributes to breast cancer, and we focus our research on understanding how this error regulation leads both to tumor emergence and how the tumor interacts with and benefits from surrounding tissue. We also hope to contribute to the development of principles for new combination treatments where at the same time you counter Notch signaling and other signal mechanisms to obtain a better and more specific treatment for breast cancer.

Breast cancer, with 7,000 new patients annually, despite improved treatment, continues to pose a major medical problem, and there are many aspects of breast cancer that we do not yet understand. In recent years, it has become increasingly apparent that an important signaling mechanism called Notch signaling is often misregulated in breast cancer. This is evident, among other things, through a connection between high Notch signaling and poor prognosis for the patient. Notch signaling is important for most of the body's organs and tissues that develop normally, but when it is mutated or expressed at too high a level, this can lead to cancer. Increased Notch signaling is linked to breast cancer, and we want to understand the role this plays in several important stages of the tumor process. In this application, we want to find out how Notch in animal models can initiate breast cancer, and what other genes are involved in this. We also want to understand how Notch affects the interaction between tumor and surrounding stroma tissue. Finally, we also want to learn more about how Notch signaling interacts with other important signaling pathways in the tumor cells, inter alia with the mechanism that handles situations with low oxygen pressure in the tissue, which often occurs in tumors. The overall and long-term aim of the project is to be able to contribute to developing new and improved therapies for breast cancer. It is becoming increasingly clear that misregulated Notch signaling contributes to breast cancer, and we focus our research on understanding how this error regulation leads both to tumor emergence and how the tumor interacts with and benefits from surrounding tissue. We also hope to contribute to the development of principles for new combination treatments where at the same time you counter Notch signaling and other signal mechanisms to obtain a better and more specific treatment for breast cancer.