Regeneration of Sinusoidal niches to preserve hematopoiesis after chemotherapy on Ageing: ReSinAge

Programme(s): H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) MAIN PROGRAMME

Topic(s): ERC-2020-COG - ERC CONSOLIDATOR GRANTS

Call for proposal: ERC-2020-COG

Funding Scheme: ERC-COG - Consolidator Grant

Grant agreement ID: 101002453

Project description

Restoring haematopoiesis in the elderly after chemotherapy

Chemotherapy remains the conventional treatment for many types of cancer. However, it presents with adverse side effects such as myelosuppression and life-threatening neutropenia, especially in elderly patients. Scientists of the EU-funded ReSinAge project are interested to investigate the role of bone marrow sinusoidal endothelial cells on haematopoietic recovery and niche regeneration after chemotherapy. The scientific team proposes to rejuvenate vascular endothelial stem cells by targeting specific transduction pathways. Moreover, they will employ a number of cutting-edge approaches to investigate the impact of such intervention strategies on survival after chemotherapy in the elderly.

Objective

Cancer is a disease of the elderly and chemotherapy remains the mainstay of treatment. The benefits of chemotherapy include increased overall survival, improvement in quality of life, and palliation of symptoms. However, older patients are more susceptible to specific toxicities of chemotherapy, like myelosuppression and life-threatening neutropenia.
Among the tissues strongly affected by chemotherapy, the bone marrow sinusoidal endothelial cells constitute the most important supportive niche for aged hematopoietic stem cells function and for myelopoietic recovery in the elderly. Up to now, few data are available about how aged sinusoidal niches regenerate upon chemotherapy damage and whether it is possible to rejuvenate vascular endothelial stem cells and improve the regeneration of the old sinusoidal niche as an effective strategy to improve HSC function and prevent myelosuppression and life-threatening neutropenia in the elderly.
Here I hypothesize that the reduced regenerative capacity of aged sinusoidal niches can be improved by rejuvenating vascular endothelial stem cells in vivo via targeting Cdc42 activity and the Notch:Jag2 signaling. The current proposal investigates whether improving the regeneration of the aged sinusoidal niche might represent an important target to enhance the hematopoietic recovery and increase the survival after chemotherapy in the elderly.
By combining several ground-breaking approaches ranging from single-cell sequencing, whole-mount bone marrow imaging, deep learning strategies for data analysis and integration, stem cell sorting techniques and specific mouse models, this research project will demonstrate that aging is not irreversible and that targeting the stem cell niche could represent an unprecedented innovative strategy to improve the regenerative capacity not only of hematopoietic stem cells.