Neuroimmune axis contribution to the pathophysiology of pulmonary hypertension

项目摘要/摘要 肺动脉高压(PH)是一种进展性疾病，会导致右心衰竭，并导致不可接受的高水平 死亡率。尽管在我们对PH的易感因素的理解上取得了重大进展，但到目前为止，我们仍然有 对其发展和进步的机械洞察力有限。因此，尽管目前的治疗方法取得了进展， 目前尚无有效的治疗方法，治疗对预后的改善也有限。因此，药物的发展 替代靶点的治疗可能会让患者受益。为此，我们已发表的和初步研究的恶魔- 水平增加激活的小胶质细胞，特别是表达TREM2的疾病相关小胶质细胞，有助于 自主脑区的神经炎症，特别是下丘脑室旁核。 Mus.这些数据告诉我们的中心假设，驻留的小胶质细胞，特别是TREM2+的激活 小胶质细胞亚型和浸润性髓系前体，促进异常的自主神经前神经元信号- 位于下丘脑室旁核的ING导致持续的交感神经激活， 这对PH来说是至关重要的。我们计划通过以下三个目标来验证这一假设：目标1将评估 促进室旁核内自主前神经元活动增加的小胶质细胞依赖机制；目的 2将评估TREM2在PH病理生理中的作用机制，探索TREM2在PH中的作用机制。 假设TREM2在小胶质细胞中的表达是增强交感神经活性的必要条件和充分条件 因此，一个潜在的治疗靶点。最后，目标3将检验慢性小胶质细胞激活的假设 导致自主神经紊乱和全身炎症增强，从而增加循环中的髓系 细胞渗透到脑室旁核等自主脑区，导致前馈循环中的神经炎症， 不断恶化的PH结局。实验将结合脑片的双光子显微镜，流式细胞术，症状- 人工消融，以及几种尖端的遗传模型。最终，我们预计这些研究的结果将与- 为更好地理解小胶质细胞和浸润性髓系前体细胞的作用机制而致敬 对PH的病理生理学的影响。总而言之，拟议的研究将产生关于 脑在肺动脉高压中的致病作用，可能是PH的一个全新靶点 治疗学。此外，安德鲁·布莱恩特博士和埃里克·克劳斯博士的强大指导以及 由资深教授组成的委员会，他们是拟议技术方面的专家，并具有广泛的 指导经验；将提供概念和方法培训，以实现研究目标和 让我为建立一个独立的研究项目做好准备。

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.