Detalhes do projeto

Description

Maintaining tissue homeostasis and proper functioning of all body tissues requires a highly functional network of blood vessels. This network enables delivery of oxygen, nutrients, and other essential blood-borne factors to cells while removing metabolic waste products(1). Endothelial cells (ECs), the cells lining the interior of blood vessels, play additional critical roles by secreting angiocrine factors that support survival and maintenance of other cell types and tissues(2,3).

Blood vessels and ECs undergo aging processes resulting in multiple changes that impact their function and lead to the pathogenesis and progression of several age-related vascular diseases, including atherosclerosis, hypertension, stroke, Alzheimer´s disease, sarcopenia, kidney and eye diseases(3–5). Recent findings demonstrated that ECs are particularly vulnerable to age-related alterations in circulating blood factors (blood-borne factors), exhibiting strong changes in their transcriptome(6–8). As a consequence of these alterations, angiocrine signaling becomes
dysregulated in ECs, leading to the onset of age-related diseases(2,9–13).

Our group has recently discovered that the activity of the transcription factor Serum Response Factor (SRF) decreases in the ECs of aged animals. We found that aging-related blood-borne factors activate SRF targets, and EC-specific inactivation of SRF causes a premature onset of age-related disease and accelerates multi-organ ageing. These preliminary data suggest that ECs are crucial homeostatic regulators that receive and transmit signals affecting organ physiology.

The main objective of this research project is to explore the systemic effects of ECs, particularly focused on its angiocrine signaling, on the regulation of aging and the onset of age-related diseases.

Using different mouse models and cutting-edge approaches, I propose to: (a) determine the impact of endothelial SRF activity on the onset of age-related diseases; (b) identify the molecular mechanisms that regulate EC response to blood-borne factors associated with healthy aging and the involved angiocrine signaling pathways; (c) establish a scientific foundation for translational approaches that aim to target ECs and promote a healthier lifespan.

The animal models are already available in the laboratory and I have ample experience on the technical approaches that will be employed in this project(14–19). Thus, this project is highly feasible, and will rapidly yield to a strong scientific output due to its innovative perspective that ECs and angiocrine factors are fundamental regulators of organ physiology, including aging.

Ultimately, this project may provide insights for therapeutic interventions in age-related diseases and promoting healthy aging, which align with the United Nations General Assembly and WHO's goals for the Decade of Healthy Aging Initiative(20).
EstadoAtivo
Data de início/fim efetiva1/04/2431/03/30

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