Disequilibrium in immune homeostasis in hypoxic pulmonary hypertension pathogenesis

About This Grant

1 Pulmonary hypertension (PH) is a progressively debilitating condition characterized by enhanced 2 vasoconstriction, vascular remodeling, and inflammation. Chronic hypoxia (CH) worsens PH outcomes 3 regardless of the underlying cause. There are no FDA-approved treatments for hypoxic PH. Therefore, there is 4 a significant unmet need to identify effective therapies to treat PH patients with hypoxemia. 5 Previous research has identified aberrant cellular and molecular pathways within the vasculature, and 6 immunoinflammatory mediators have been implicated in PH pathogenesis. Still, little is known of the identity and 7 role of the self-antigens responsible for the inflammatory response. This knowledge gap is significant because 8 T regulatory cell (Treg) dysfunction is present in PH. While required to maintain immune homeostasis, Tregs can 9 become pathogenic and react against self-antigens. Thus, our long-term goal is to define the mechanisms of self- 10 reactive chronic inflammation that contribute to PH pathogenesis to guide the future development of effective, 11 targeted therapies. 12 Our group was the first to demonstrate that CH elicits collagen V (col V)-reactive memory T helper 17 (col V- 13 reactive TH17) cells. We recently reported the novel finding that CH causes a decrease in active Tregs and 14 increases Tregs expressing markers of TH17 cells (exTregs-TH17 cells). Thus, we hypothesize that hypoxia- 15 induced Treg dysfunction and reprogramming of exTreg into col V-reactive TH17 cells promotes pulmonary 16 vascular dysfunction through cytokine and cell-cell interactions. 17 To test our central hypothesis, we propose the following aims: 18 Aim 1: Identify the mechanism(s) by which CH causes immune dysregulation, contributing to PH 19 pathogenesis. 20 Aim 2: Determine how col V-reactive TH17 cells impact the transcriptome and function of neighboring 21 vascular cells, contributing to vascular dysfunction in PH. 22 We expect discoveries derived from this project will facilitate, in part, the identification of novel disease 23 biomarkers and the design of antigen-specific, Treg-based therapies to reduce nonspecific generalized 24 immunosuppression caused by polyclonal Treg administration and aid in PH treatment for which effective 25 therapies are limited.