Inflammation and Therapy for Respiratory Virus Infection

正在进行的研究重点是探索急性呼吸道病毒感染的病理炎症反应，并利用这些信息来制定创造性的策略，以规避这种疾病的致命后遗症的特点。 在2020财年，我们贡献了一（1）份原创研究手稿： 制造商编号1： 一个自然的小鼠模型揭示了系统性毛细血管渗漏综合征的遗传决定因素 （克拉克森病）。 系统性毛细血管渗漏综合征（SCLS，克拉克森病）是一种病因不明的疾病，其特征在于反复发作的蛋白质和液体血管渗漏进入外周组织，导致全身水肿和水肿性休克。SCLS的病理机制和遗传基础仍不清楚。在这里，我们确定了一个近交系小鼠品系，SJL，它概括了SCLS的主要特征，包括对组胺和感染引发的血管渗漏的敏感性。我们将这种特性命名为“组胺超敏反应”（Hhs/Hhs），并将其定位于6号染色体。Hhs与人类中与SCLS最密切相关的基因组位点同线（3p25.3），揭示了发展血管通透性过高的倾向具有在人类和小鼠之间保守的强遗传成分，并为SCLS提供了天然存在的动物模型。Hhs的遗传分析可能揭示不仅有助于SCLS，而且还有助于更普遍的血管屏障功能的正常和失调机制的正向候选基因。 我们的贡献：我们提供的专业知识和试剂，促进了探索这些小鼠对急性呼吸道病毒感染的反应，急性呼吸道病毒感染是引起该综合征血管渗漏的主要病理生理因素之一。 参考：Raza A，Xie Z，Chan EC，Chen WS，Scott LM，Robin Rupsch A，Krementsov DN，Rosenberg HF，Parikh SM，Blankenhorn EP，Teuscher C，Druey KM. 2019. Commun Biol.2：398.

Ongoing research focuses on the exploration of pathologic inflammatory responses to acute respiratory virus infection and the use of this information to develop creative strategies to circumvent the lethal sequelae characteristic of this disease. In Fiscal year (FY) 2020, we contributed to one (1) original research manuscript: Manuscript #1: Title: A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease). The systemic capillary leak syndrome (SCLS, Clarkson disease) is a disorder of unknown etiology characterized by recurrent episodes of vascular leakage of proteins and fluids into peripheral tissues, resulting in whole-body edema and hypotensive shock. The pathologic mechanisms and genetic basis for SCLS remain elusive. Here we identify an inbred mouse strain, SJL, which recapitulates cardinal features of SCLS, including susceptibility to histamine- and infection-triggered vascular leak. We named this trait "Histamine hypersensitivity" (Hhs/Hhs) and mapped it to Chromosome 6. Hhs is syntenic to the genomic locus most strongly associated with SCLS in humans (3p25.3), revealing that the predisposition to develop vascular hyperpermeability has a strong genetic component conserved between humans and mice and providing a naturally occurring animal model for SCLS. Genetic analysis of Hhs may reveal orthologous candidate genes that contribute not only to SCLS, but also to normal and dysregulated mechanisms underlying vascular barrier function more generally. Our contribution: We provided expertise and reagents that facilitated an exploration of the responses of these mice to an acute respiratory virus infection, one of the major pathophysiologic factors that incite vascular leak in this syndrome. Ref: Raza A, Xie Z, Chan EC, Chen WS, Scott LM, Robin Eisch A, Krementsov DN, Rosenberg HF, Parikh SM, Blankenhorn EP, Teuscher C, Druey KM. 2019. Commun Biol. 2:398.