NIH grant: Characterization of RGS Function and Signaling (1R01HL182020-01A1)

retained text

NIH grant 1R01HL182020-01A1: Characterization of RGS Function and Signaling
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Fadi T Khasawneh. Award: $761981.
Start: 2026-08-15T00:00:00.
The role and mechanistic regulation of one of the key regulators of G-Protein Coupled Receptors (GPCRs),
specifically the regulator of G-protein signaling (RGS) proteins in platelet biology remains poorly understood. Thus,
while evidence exists in support of a role for RGS proteins in platelets, studies thus far- outside of our work- have
been limited and/or are generally correlative in nature. This derives from lack of appropriate pharmacological tools
that target the RGS proteins that are known to be expressed in platelets (i.e., RGS10, 16 and 18), nature
of/limitations in the studies performed, and lack thereof. Therefore, the present application proposes experiments
that address mechanistic aspects of the regulatory biology and signaling machinery of the platelet RGS proteins,
including in the context of sepsis-related thrombosis. Specifically, the proposed studies will first characterize the
function of RGS proteins. This will include their role in thrombogenesis and aggregation, as well as under non-
canonical agonist stimulatory conditions. Moreover, whether the RGS proteins play a role in mediating inhibitory
signaling will also be examined. The second set of studies will characterize RGS signaling machinery and
regulation. Since RGS proteins were found to be regulated by phosphorylation and dephosphorylation events, their
phosphorylation state under resting and activation conditions, in response to inhibitory and stimulatory signaling,
will also be characterized. Furthermore, whether RGS proteins directly interact with GPCRs and/or GPs, under
resting and agonist-stimulation conditions will be examined. In addition, the regulation of RGS proteins by the
scaffold proteins; and how they modulate complex formation, in platelets, will also be studied. The third and last
series of experiments will investigate the mechanistic role of RGS proteins in sepsis-dependent thrombosis. While
the role of the coagulation system in sepsis-dependent thrombosis is well established, that of platelets is not as
well-understood or studied. Thus, the expression levels of RGSs in sepsis samples will be assessed. Moreover,
the role of RGS proteins in promoting sepsis-dependent thrombosis will be studied, along with their role in
neutrophil extracellular traps (NETs) formation. Finally, whether RGSs are involved in regulating chemokine
GPCRs in a toll-like receptor (TLR) dependent manner in platelets is unknown but will be investigated. To achieve
the goals of these studies, a genetic approach (conditional deletion mice) will be undertaken, and human blood,
as well as samples, including from sepsis patients will be utilized. Collectively, these studies will provide novel,
fundamental, and mechanistic information concerning multiple aspects of RGS biology and signaling, in the context
of platelets, sepsis-associated thrombosis and sex.

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