人类Hippo激酶Mst1基因缺失导致机体严重的真菌等病原感染但其病理机制尚未阐明。申请人前期发现与Mst1互作分子NDR1/2激酶的敲除小鼠对真菌感染易感性比Mst1缺失更显著，由此推测Mst1很可能通过调控NDR1/2激酶活性来实现其抗感染的免疫应答和宿主防御。本项目拟从分子、细胞、动物模型和临床样本分析等多个层次，系统研究NDR1/2激酶在机体抗感染应激中的免疫调节与宿主防御的作用机制与功能，旨在阐明NDR1/2激酶对固有免疫细胞增殖、发育、分化的影响，鉴定真菌等病原感染激活NDR1/2激酶的模式识别受体，探究其在抗原提呈细胞中的功能机制，阐明其在机体抗感染过程中的功能和作用，解析其失调与人类感染性疾病发病的相关性。本项研究将有助揭示人类Mst1功能缺失突变导致机体严重感染的致病机理，阐明机体抗感染的新型调控机制和关键效应分子，提供抗感染药靶，研究具有重要的科学意义与临床价值。

Innate and adaptive immune responses are well coordinated by sets of molecules and receptors that act to generate the most effective form of immunity for protection against fungal pathogens. Dendritic cells (DCs) are uniquely able to initiate and control the immune response to these pathogens. However, the underlying mechanisms by which signaling changes occurring in DC modulate the activation state of DC cells remain largely unclear. Our lab mainly focuses on understanding immune regulation and infection disease, and have several exciting discoveries which have been published in the top ranking journals including Nature immunology, Immunity, Science Translational Medicine, Nature Commun, Cell Reports and J Exp Med. We recently have revealed the key regulatory role of kinases Mst1/2, a core component of Hippo signaling, in both adaptive and innate immunity. Clinical manifestations of human Mst1 deficiency comprise recurrent and severe infections including warts, fungal and bacterial infections. Recent studies revealed that Mst1/2 regulate immune function through kinases Ndr1/2. Hence, we aim to determine the role of Ndr1/2 in DCs in the manipulation of the immune response to fungi including the innate response in DC to fungi by Ndr1/2-mediated inflammatory mediator production; second, how Mst1/2-mediated signals, decode the fungus-associated information and translate it in qualitatively different Th responses, and third, whether Ndr1/2-mediated signals are invovled in containing and dampening inflammatory responses by tolerization through the induction of Treg. These studies may provide an opportunity for improved strategies for the prevention and management of fungal diseases in immunocompromised patients.