Friday, May 3, 2024
5/3/2024
PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (PH) is a progressive disease leading to right heart failure and an unacceptably high mortality rate. Despite major milestones in our understanding of predisposing factors to PH, to date, we still have limited mechanistic insight into its development and progression. Thus, despite advances in current therapies, there is no available cure and treatment has limited improvement in outcome. Therefore, development of drug treatments with alternate targets may benefit patients. To this end, our published and preliminary studies demon- strate increased activated microglia, specifically TREM2-expressing disease-associated microglia, contribute to neuroinflammation in autonomic brain regions, particularly the paraventricular nucleus (PVN) of the hypothala- mus. These data informed our central hypothesis that activation of resident microglia, especially TREM2+ microglia subtype and infiltrated myeloid precursors, promotes aberrant preautonomic neuronal signal- ing in the paraventricular nucleus of the hypothalamus leading to sustained sympathetic activation, which is critical to PH. We plan to test this hypothesis via the following three aims: Aim 1 will evaluate the microglia-dependent mechanisms that contribute to increased preautonomic neuron activity within the PVN; Aim 2 will evaluate the mechanism by which TREM2 contributes to PH pathophysiology, exploring the working hy- pothesis that TREM2 expression within microglia is necessary and sufficient for augmented sympathetic activity and thus, a potential therapeutic targeted. Finally, Aim 3 will test the hypothesis that chronic microglia activation leads to dysautonomia and enhanced systemic inflammation, with consequently increase in circulating myeloid cells infiltration to autonomic brain regions such as PVN, contributing to neuroinflammation in a feedforward loop, worsening PH outcomes. Experiments will combine 2-photon microscopy in brain slices, flow cytometry, sympa- thetic ablation, and several cutting-edge genetic models. Ultimately, we expect results of these studies to con- tribute to better understanding of the mechanism whereby microglia and infiltrated myeloid precursors contribute to the pathophysiology of PH. Collectively, the proposed studies will lead to novel information regarding the brain’s pathogenic contribution to pulmonary hypertension, which may represent an entirely novel target for PH therapeutics. In addition, strong mentorship by Drs. Andrew Bryant and Eric Krause, as well as a Mentoring Committee comprised of established professors, who are experts in the proposed techniques and have extensive mentoring experience; will provide conceptual and methodological training, to achieve the research goals and prepare me to establish an independent research program.
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