细胞内钙离子浓度广泛调控着各种生命活动，环腺苷二磷酸核糖（cADPR)是可以释放内质网Ca2+的重要第二信使，它由辅酶NAD+环化而成。CD38是在哺乳动物细胞中最早发现的催化该反应的环化酶，我们在研究CD38抑制剂的过程中，偶然发现抑制剂CZ-x可以激活一条CD38非依赖的cADPR合成通路，后证实它激活的是一个神经退变相关蛋白SARM1，进一步发现CZ-x同源的内源小分子NMN在体外也能激活SARM1。本项目有三个研究目标：1）揭示激活后SARM1的酶学性质，与CD38的异同；2）阐明NAD+合成前体NMN激活SARM1的分子机制；3）研究SARM1活化引起细胞行为变化，例如钙离子释放、细胞死亡及轴突退化等。本项目的顺利进行将揭示NMN作为內源信号分子的机制，利用CZ-x揭示SARM1的活化机制，为神经退行性疾病的药物开发提供理论依据。

Intracellular Ca2+ regulates various cell functions. Cyclic ADP-ribose (cADPR) is an important second messenger mediating Ca2+ mobilization from the ER store. cADPR is derived from the coenzyme, NAD+, catalyzed by the ADP-ribosyl cyclases. CD38 is the first-discovered enzyme in mammalian cells, which can catalyze this cyclization reaction. Recently, we accidentally found an inhibitor of CD38, CZ-x could activate a CD38-independent cADPR-synthesizing pathway, which was proven to be the newly-discovered enzyme, SARM1. We revealed that the endogenous homologue of CZ-x, NMN could activate SARM1 in vitro, but not in cellulo, due to the cell impermeability. The project has three aims: 1) to characterize the enzymatic activities of the activated SARM1 and compare with those of CD38; 2) to elucidate the activation mechanism of SARM1 induced by NMN, a precursor of NAD+ synthesis; 3) to study the cellular behaviors including Ca2+ releasing, cell death or axonal degeneration, etc upon SARM1 activation. .Our data might provide a possible mechanism that an NAD+ metabolite, NMN, alters the metabolism pathway of NAD+, by activating an NAD+-consuming enzyme SARM1 and shed light on the molecular mechanism of axonal degeneration or other related cell death, which will provide insight for the drug development against the neuronal degenerative diseases.