Publication: Identification of molecular signatures and potential therapeutics in pulmonary hypertension via systems biology approaches
Abstract
Pulmoner arteriyel hipertansiyon (PAH), sağ kalp kateterizasyonu ile ölçülen ortalama pulmoner arter basıncının istirahat halinde 20 mmHg'nin üzerinde olması ile karakterize, pulmoner hipertansiyonun nadir ancak ölümcül bir formudur. Bu durum ilerleyici pulmoner vasküler yeniden şekillenme ve sağ ventrikül yetmezliği ile karakterizedir. Hastalığa özgü semptomların olmaması erken tanı için önemli bir zorluk teşkil etmektedir ve hastalık genellikle mevcut vazodilatör bazlı terapötik müdahalelere rağmen ilerleme göstermektedir. Sonuç olarak, durumun erken teşhisi için moleküler biyobelirteçlerin ve daha etkili tedavisi için terapötik hedeflerin belirlenmesi büyük önem taşımaktadır. Bu tez kapsamında, birden fazla PAH hasta kohortundan alınan transkriptom veri setlerinin meta-analizi gerçekleştirilmiştir. Anlatımı istatistiksel olarak önemli ölçüde değişim gösteren genler GEO2R aracı kullanılarak tanımlanmış ve önemli fonksiyonel modülleri belirlemek için ortak ifade ağları yeniden yapılandırılmıştır. PAH varlığında, immün düzenleme, vasküler yeniden şekillenme ve proliferatif sinyal yolaklarında bozulma gözlenmiştir. ARIH1, LILRB2 ve SECISBP2L gibi güçlü tanı performansı gösteren anahtar genler potansiyel biyobelirteçler olarak tanımlanmıştır. Ayrıca, anahtar genleri hedef alan FDA onaylı ilaçları belirlemek için hesaplamalı ilaç yeniden konumlandırma yöntemi uygulanmıştır. Belirlenen ilaçlar arasında metformin, simvastatin, vorinostat ve docetaksel, mekanistik açıdan hastalıkla ilişkili olmaları ve önceki çalışmalardan elde edilen destekleyici kanıtların varlığı temelinde özellikle dikkate değer olarak tanımlanmıştır. Öte yandan ilaç yeniden konumlandırma analizleri ile belirlenen bazı farmasötik ajanların (örn. dasatinib) PAH ile ilişkili yolaklara belirli bir derecede yakınlığı olduğu gösterilmiş olsa da, bunların bilinen olumsuz kardiyovasküler etkileri dikkatli yorumlama gerekliliğinin altını çizmektedir. Bu çalışma, PAH için yeni moleküler imzalar ve farmakolojik hedefler önermekte ve gelecekteki deneysel doğrulamalara ve klinik uygulamalara temel oluşturabilecek kapsamlı bir hesaplamalı çerçeve sunmaktadır.
Pulmonary arterial hypertension (PAH) is a rare but lethal form of pulmonary hypertension, characterised by a mean pulmonary artery pressure above 20 mmHg at rest, as measured by right heart catheterisation. The condition is characterised by progressive pulmonary vascular remodelling and right ventricular failure. The absence of disease-specific symptoms poses a significant challenge to early diagnosis, with the disease often progressing despite current vasodilator-based therapeutic interventions. Consequently, the identification of molecular biomarkers for the early diagnosis of the condition, and of therapeutic targets for the more effective treatment thereof, is of paramount importance. In the scope of this thesis, meta-analysis of transcriptome datasets from multiple PAH patient cohorts was employed. Differentially expressed genes were determined via GEO2R tool, and co-expression networks were reconstructed to elucidate pivotal functional modules. In the presence of PAH, disruption in immune regulation, vascular remodelling, and proliferative signalling pathways was observed. Key genes showing strong diagnostic performance such as ARIH1, LILRB2, and SECISBP2L were identified as potential biomarkers. Furthermore, a computational drug repurposing pipeline was utilised to prioritise FDA-approved drugs targeting the key genes. Among the identified drugs, metformin, simvastatin, vorinostat, and docetaxel were identified as being particularly noteworthy on the basis of their mechanistic relevance and the existence of supporting evidence from prior studies. While certain pharmaceutical agents (e.g., dasatinib) identified by drug repurposing analyses have been shown to have a certain degree of proximity to PAH-related pathways, their known adverse cardiovascular effects underscore the necessity for cautious interpretation. The present study proposed novel molecular signatures and pharmacological targets for PAH and provided a comprehensive computational framework that may support future experimental validation and clinical translation.
Pulmonary arterial hypertension (PAH) is a rare but lethal form of pulmonary hypertension, characterised by a mean pulmonary artery pressure above 20 mmHg at rest, as measured by right heart catheterisation. The condition is characterised by progressive pulmonary vascular remodelling and right ventricular failure. The absence of disease-specific symptoms poses a significant challenge to early diagnosis, with the disease often progressing despite current vasodilator-based therapeutic interventions. Consequently, the identification of molecular biomarkers for the early diagnosis of the condition, and of therapeutic targets for the more effective treatment thereof, is of paramount importance. In the scope of this thesis, meta-analysis of transcriptome datasets from multiple PAH patient cohorts was employed. Differentially expressed genes were determined via GEO2R tool, and co-expression networks were reconstructed to elucidate pivotal functional modules. In the presence of PAH, disruption in immune regulation, vascular remodelling, and proliferative signalling pathways was observed. Key genes showing strong diagnostic performance such as ARIH1, LILRB2, and SECISBP2L were identified as potential biomarkers. Furthermore, a computational drug repurposing pipeline was utilised to prioritise FDA-approved drugs targeting the key genes. Among the identified drugs, metformin, simvastatin, vorinostat, and docetaxel were identified as being particularly noteworthy on the basis of their mechanistic relevance and the existence of supporting evidence from prior studies. While certain pharmaceutical agents (e.g., dasatinib) identified by drug repurposing analyses have been shown to have a certain degree of proximity to PAH-related pathways, their known adverse cardiovascular effects underscore the necessity for cautious interpretation. The present study proposed novel molecular signatures and pharmacological targets for PAH and provided a comprehensive computational framework that may support future experimental validation and clinical translation.