Pathomechanisms of native tear protein complexes in dry eye syndrome

• Applicant: Dr. Natarajan Perumal
• Subject Area: Ophthalmology ; Biochemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452535756

Dry eye syndrome (DES) is an allotropic clinical dysfunction of the tear film. Although the general tear proteome alterations have been well-studied, specific molecular alterations attributed to different DES subgroups remain largely unknown. Our preliminary studies have provided compelling evidence that the pathogenesis of DES is specifically correlated to the breach in the protein-protein interactions of major tear proteome complexes in their native conformation. Therefore, this study aims to unravel the underlying pathomechanistic signaling networks and intricate native proteome regulation in tears of DES patient subgroups by addressing three major hypotheses. The first hypothesis is tear protein complexes play crucial roles in maintaining the tear film homeostasis in healthy individuals and their interactions are breached in DES. This investigation will characterize the native human tear protein complexes in healthy individuals and determine how these complexes are compromised in different DES subgroups. Next, we have demonstrated that there are inter-individual proteome alterations in the tears of DES patients, which are correlated to particular clinical traits. Thus, the second hypothesis is the regulation of different protein complexes in DES subgroups are correlated to the clinical attributes and severity of disease. This analysis will characterize the correlation between the expression profiles of native tear proteins and clinical attributes in DES, while providing an in-depth insight into the inter-individual variations employing an absolute quantification with mass spectrometric multiple reaction monitoring-based strategy. The potential outcome of this study would be an important step to further understand the pathophysiology of DES while laying groundwork towards personalized medicine in DES. Hyperosmolarity is the key initiation factor that triggers ocular surface inflammation, oxidative stress and apoptosis in DES patients. Hence, the final hypothesis to be tested is exogenous supplementation of specific native protein complex(es) on the ocular surface is able to restore homeostasis, thereby breaking the vicious cycle that perpetuates DES. This subproject will investigate the potential protective and regenerative function(s) of selected proteins in tear complex(es) on the corneal epithelial cell line. The findings emerging from this study are projected to highly facilitate future research endeavors in the development of synthetic therapeutic peptides comprising the major components of native tear complex(es). The ultimate outcome of this investigation is envisioned to elucidate the missing link between native tear proteome and the maintenance of human tear homeostasis, which will be instrumental for future translational efforts for improved clinical management of this pathology and development of treatment paradigms in a highly personalized manner.

• DFG Programme: Research Grants