TAM IN AMD

Role of TAM signaling in Retinal Homeostasis

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 Obiettivo del progetto (Objective)

'Macular and retinal degeneration are common blinding conditions which affect approximately 30% of individuals aged 75 years, and pose considerable socioeconomic burden. Lack of the daily phagocytosis of photoreceptor outer segments (POS) by Retinal Pigment Epithelium (RPE) cells is the basis of such retinal degeneration (RD). This proposal aims to characterize the role of TAM receptor Tyrosine Kinase signaling in maintaining healthy retinal homeostasis. TAM receptors (Tyro3, Axl, Mer) are homeostatic regulators of the Immune, Reproductive and Nervous systems. Mer knockout mice show normal retinal structure at birth; however, at three weeks of age photoreceptors (PRs) begin to undergo apoptotic death, and by 8 weeks the entire PR population is eliminated, causing blindness. Mer mutations in rats and humans, leads to impaired vision and blindness. The two TAM ligands ProS and Gas6 are expressed in the eye. In-vitro experiments have identified Gas6 as the relevant ligand necessary to activate PR phagocytosis, but adult Gas6 KO mice have no PR degeneration, suggesting a role for ProS. To investigate whether ProS is a TAM agonist leading to PR phagocytosis, I developed a unique ProS conditional knockout mouse model. Preliminary results indicate that mice lacking ProS in the eyes show mild RD, suggesting ProS is a functional ligand in-vivo. Deleting both ligands causes severe RD, implying synergism between both ligands. This novel evidence illuminates the mechanism of TAM signaling in-vivo suggesting ligand hetero-dimerization. Using the newly generated mouse model, I propose to characterize the detailed expression pattern of TAM receptors and ligands in the eye, to establish a role for ProS in retinal homeostasis, and to utilize the unique model to better understand the TAM signaling mechanism. A linkage between ligand levels and RD will be tested, and if found, ProS and Gas6 may serve as early biomarkers for retinal degenerative disease.'

Introduzione (Teaser)

Macular and retinal degeneration commonly cause blindness in aged people, posing considerable socioeconomic burden on society. A four-year study focused on understanding the mechanism of healthy retinal homeostasis.

Descrizione progetto (Article)

Photoreceptors are the light-sensitive neurons in the eye that enable vision. Their degeneration underlies age-related macular degeneration (AMD), currently affecting over 20 million Europeans. The project 'Role of TAM signalling in retinal homeostasis' (TAM IN AMD) aimed to compare photoreceptor function during health and degeneration. Specifically, the aim of the project was to understand the functioning of the tyrosine kinase receptors of the TAM family in the retina.

Signalling through TAM receptors (Tyro3, Axl, and Mer) is essential for maintaining a functional retina. The mechanistic aspects of TAM signalling, involving TAM ligands (PROS1 and GAS6) are mostly unclear. The project detected that retinal expression of Gas6 exceeded that of PROS1 20 times, suggesting its greater importance, but results were surprising, showing that PROS1 is critical to retinal health.

The scientists studied the contribution of PROS1 to retinal health using genetically engineered mice. While deletion of PROS1 or Gas6 alone was not sufficient to cause retinal degeneration, deletion of both Gas6 and PROS1 resulted in severe retinal degeneration. This effect was similar to one caused by deletion of the TAM receptor Mer. A first, the results indicate that PROS1 is a functional ligand for TAM receptors in vivo, crucial for photoreceptor viability and retinal health.

Finally, the project evaluated the potential use of PROS1 levels in the eye as a biomarker for retinal degenerative disease. A pilot study tested the aqueous humour samples from patients with retinal degenerative disease and healthy individuals. The results indicated a high level of PROS1 in all healthy individuals, while the majority of diseased patients had low levels of PROS1. This suggests that low levels of PROS1correlate with retinal degenerative disease. A broader study involving more subjects is needed to confirm this hypothesis.

Understanding the causes and mechanisms of retinal degenerative diseases help in developing new diagnostics and treatments.