Open Research Projects, Research

The role of the primary cilium in the physiological autoregulation of the pulmonary vasculature

Prinicipal Investigator

Prof. Dr. Wolfgang Kübler
Prof. Dr, Robert Szulcek

Scientific interest within the context of the graduate college:

Maintenance or restoration of vascular homeostasis are critical determinants of health throughout life. Of late, the primary cilium has been identified as a key regulator of vascular homeostasis and regeneration. While impairment of primary ciliary structure and signaling can promote vascular disease and vascular remodeling, strategies aiming to preserve or restore ciliary function emerge as novel therapeutic approaches to maintain vascular health.

Project description:

Physiologically, homeostatic signaling in response to biochemical and biomechanical cues within the pulmonary vascular wall warrants the integrity of the vascular structure of the lung and allows for its adaptation to changing requirements throughout life. Dysregulated signaling in or between pulmonary artery endothelial and smooth muscle cells, on the other hand, causes progressive adverse remodeling of the pulmonary vasculature, resulting in increased pulmonary vascular resistance, pulmonary hypertension, and ultimately death due to right heart failure. Understanding the cellular signaling mechanisms that maintain or restore vascular homeostasis in the lung is therefore critical for the prevention or therapy of pulmonary hypertension, and for the preservation of an intact vasculature throughout life up to an old age.

Ongoing research in our group has identified the primary cilium as a novel key regulator of vascular homeostasis in the lung. Unlike the motile cilia found e.g. on the respiratory epithelium or in the Fallopian tube, the primary cilium is a singular organelle (one per each cell) that is found on almost every cell type in the body. The primary cilium extends as a protrusion of the cell membrane into the extracellular space where it functions as a mechano- and chemosensor, while its base acts as a hub for numerous cellular signaling pathways. We have shown that the primary cilium maintains the cells of the pulmonary vasculature in a physiological quiescent state. Loss of the primary cilium, however, causes pathological proliferation and migration of both cell types. Importantly, we have identified such loss of the primary cilium as a hallmark of pulmonary blood vessels in patients with pulmonary hypertension. These findings fuel the intriguing hypothesis that strategies aiming to preserve or restore primary cilium structure and function may present a novel therapeutic approach to maintain lung vascular health and to reverse maladaptive vascular remodeling. In order to test this hypothesis, the present project will address the following questions:

Question 1: Which mechanisms regulate the integrity of the primary cilium in lung vascular endothelial and smooth muscle cells? Based on previous work by us and others, we will focus here specifically on signaling axes via mammalian target of rapamycin (mTOR) and aurora kinase A. Specifically, we will test whether pharmacological or genetic modulation of these pathways can maintain primary ciliary integrity in preclinical models of pulmonary hypertension.

Question 2: Can strategies aimed to restore ciliary integrity preserve lung vascular homeostasis? We have recently patented a novel intervention for rescue of the primary cilium in pulmonary hypertension. We will test whether this strategy, as well as interventions identified in Aim 1 can restore vascular homeostasis in preclinical models of pulmonary hypertension both in vitro and in vivo.

The project will be conducted at the Institute of Physiology at the Campus Mitte under close supervision by the PI and Co-PI and with the support of a dedicated research group incl. several postdocs and technical personnel, as well as several international collaborators in Europe, USA, Canada, and China. All required methods are established. The graduate student is expected to present his/her work at international conferences, and to publish the results as a full manuscript in a major peer-reviewed scientific journal.

Application details

References

  1. Fan Y, Gu X, Zhang J, […], Solymosi P, Kwapiszewska G, Kuebler WM. TWIST1 drives smooth muscle cell proliferation in pulmonary hypertension via loss of GATA-6 and BMPR2. Am J Respir Crit Care Med. 2020; 202: 1283-1296. doi: 10.1164/rccm.201909-1884OC.
  2. Dummer A, Rol N, Szulcek R, […], DeRuiter MC, Goumans MJ, Hierck BP. Endothelial dysfunction in pulmonary arterial hypertension: loss of cilia length regulation upon cytokine stimulation. Pulm Circ. 2018; 8: 2045894018764629.doi: 10.1177/2045894018764629.