Yann Grobs

Scholarships:

• 2021 Loretta Chu Memorial PH Research Scholarship

• 2022 Paroian Family PH Research Scholarship

• 2023 Paroian Family PH Research Scholarship

• 2024 Paroian Family PH Research Scholarship

Faculty of Medicine, Laval University, Quebec

Under the supervision of François Potus

About Yann Grobs

From Montpellier (France), Yann obtained a bachelor's degree in health biology before specializing in microbiology and immunology during his master's degree at the University of Montpellier II. During an internship at the Research and Development Institute (IRD) on the genetic diversity of HIV, he developed a particular interest in translational research and, more particularly, in the physiology of the cardiovascular and respiratory systems. Pulmonary arterial hypertension (PAH) is one of the complications of an HIV infection. Yann enthusiastically joined the PAH group of Quebec led by Dr. Sébastien Bonnet and Dr. Steeve Provencher. After completing his Ph.D. under the supervision of Dr. Bonnet, Yann joined the lab of Dr. François Potus as a post-doctoral fellow.

Projects:

P300/CBP a potential therapeutic target to cure pulmonary arterial hypertension (2021)

Project description: Pulmonary arterial hypertension (PAH) is a deadly and incurable vascular disease. This disease affects the pulmonary arteries (PAs) that carry the blood from the heart to the lung. Pulmonary arteries are crucial for the reoxygenation of the blood. Like in cancer, cells of pulmonary artery walls multiply faster than normal and contribute to pulmonary artery obstruction. This obstruction increases pressure in this vessel leading to fatal cardiac dysfunction.

We identified P300 as a factor implicated in genes expression. In cancer, its overexpression induces an increase in cells’ proliferation.

Similarly, we believe that this factor is involved in abnormal pulmonary arterial hypertension cell proliferation. We demonstrated that p300 is increased in pulmonary arterial hypertension patients compared to non-PAH patients. In a PAH rat model, we showed that p300 treatment decreases pulmonary artery cell proliferation and improves survival. We propose investigating further p300 function in general, which will benefit several diseases and pulmonary arterial hypertension development understanding. Interestingly, a P300 treatment is currently in clinical trials for the treatment of cancers. Therefore, our study has a high translational impact, potentiating the development of a novel treatment strategy from the laboratory to improve pulmonary arterial hypertension patient quality of life.

ATP citrate lyase orchestrates metabolic and epigenetic modification in pulmonary arterial hypertension (2022)

Pulmonary arterial hypertension (PAH) is a deadly and incurable vascular disease. This disease affects the pulmonary arteries (PAs) that carry the blood from the heart to the lung for reoxygenation. Like in cancer, cells of pulmonary arteries multiply faster than normal and contribute to pulmonary artery obstruction. This obstruction increases pressure in this vessel leading to fatal cardiac dysfunction.

The nucleo-cytoplasmic enzyme ATP Citrate Lyase (ACLY) has recently emerged as a key player and therapeutic target in cancer by favouring the Warburg effect, lipid synthesis and chromatin remodelling. We demonstrated that ACLY is overexpressed in pulmonary arterial hypertension patients and PAH-induced animal models, respectively, compared to control patients and control animals. In pulmonary arterial hypertension animal models, we demonstrated that ACLY inhibition prevents pulmonary arterial hypertension development and improves survival in animals with well-established pulmonary arterial hypertension.

We propose further investigating ACLY function in general, which will benefit several diseases and the understanding of pulmonary arterial hypertension development. Interestingly, ETC1002 (ACLY inhibitor) treatment is currently in clinical trials for the treatment of hypercholesterolemia. Our study has, therefore, a high translational impact, potentiating the development of a novel treatment strategy from the laboratory to improve pulmonary arterial hypertension patients' quality of life. Indeed, this project was published in Science Translational Medicine.

Implication of APEX1 in Pulmonary Arterial Hypertension (2023)

Pulmonary arterial hypertension (PAH) is a deadly and incurable disease. Despite recent progress in our understanding of the pathophysiological mechanisms, lung transplantation is the only therapy in end-stage pulmonary arterial hypertension. Pulmonary arterial hypertension is characterized by an obstruction of blood flow in pulmonary arteries due to vessel wall thickening, leading to vascular resistance and right heart failure. Cells from the wall of pulmonary arteries feature a phenotype like cancer cells; in other words, they have a greater capacity to multiply rapidly.

A protein called APEX1, involved in DNA repair and gene expression activation, is found to be overexpressed in pulmonary arterial hypertension cells. Our research shows elevated APEX1 levels in both pulmonary arterial hypertension patients and animal models, as well as a correlation with disease severity. This provides strong evidence implicating APEX1 in the development of pulmonary arterial hypertension. Thus, we propose determining whether elevated APEX1 expression has a detrimental function. This research is designed to advance biomedical knowledge, significantly impact our understanding of the pathogenesis of pulmonary arterial hypertension, and increase our ability to treat the disease.

Exploring the Role of Circadian Rhythms and Rev-Erb in the Pathophysiology of Pulmonary Arterial Hypertension (2024)

Mounting evidence suggests that circadian rhythms—our body's internal clock—play a significant role in the development of pulmonary arterial hypertension (PAH). Disruptions in these rhythms can affect various biological processes, including inflammation and cell growth, contributing to pulmonary arterial hypertension pathology. This study explores the role of circadian clock genes, particularly Rev-Erbα, as potential therapeutic targets in pulmonary arterial hypertension.

Rev-Erbα, a core circadian regulator influenced by iron-enriched heme, is hypothesized to be downregulated in pulmonary arterial hypertension due to iron deficiency. We investigate Rev-Erbα's expression in pulmonary arterial hypertension patients and models, examining its effect on proliferation, apoptosis, metabolism, and inflammation of pulmonary artery smooth muscle cells (PASMCs). Pharmacological activation of Rev-Erbα with SR9011 shows promise in reducing pulmonary artery smooth muscle cell proliferation and remodeling in rat models, suggesting circadian biology's relevance in pulmonary arterial hypertension. The study proposes integrating chrono-therapeutics to optimize treatment efficacy, highlighting Rev-Erbα's central role in pulmonary arterial hypertension pathogenesis and its potential for novel therapeutic strategies.

Insights from this research could lead to innovative treatment strategies that align with the biological rhythms of patients, improving outcomes for those affected by pulmonary arterial hypertension.