Molecular mechanisms of disturbed thermoregulation exemplified by Crisponi syndrome

人类体温调节的机制仍然没有完全了解。患有罕见的Crisponi综合征的患者在婴儿期出现高热危象，在青春期出现寒冷引起的出汗。在以前的研究中，我们确定CRLF 1基因突变是这种综合征的原因。最近，我们在具有“Criponi样”表型的患者中另外鉴定了KLHL 7的突变。我们可以证明Crisponi表型的严重程度取决于个体突变的CRLF 1蛋白的分泌能力，并且患者中冷诱导的出汗与血浆去甲肾上腺素水平的增加相关。此外，最近，我们发现多巴胺-β-羟化酶，去甲肾上腺素合成的关键酶，在CRLF 1阴性神经元的表达增加。在拟议的项目中，我们将研究KLHL 7的缺乏是否也会导致中枢去甲肾上腺素合成增加。在这方面，我们将采用神经元KLHL 7阴性细胞系，其由人诱导多能干细胞产生。 此外，我们将使用条件性敲除小鼠模型，其中Crlf 1在中枢神经系统的神经元中被敲除。在这个小鼠模型中，我们将研究CRLF 1缺乏对中枢去甲肾上腺素合成、神经元功能和体温调节的影响。 该项目不仅将建立一种新的体温调节紊乱的动物模型，而且还将确定新的治疗靶点来治疗Crisponi综合征。

Mechanisms of human thermoregulation are still not completely understood. Patients suffering from the rare Crisponi Syndrome develop hyperthermic crises in infancy and cold-induced sweating during adolescence. In previous studies, we identified mutations in the CRLF1 gene as the cause of this syndrome. Recently, we additionally identified mutations in KLHL7 in patients with a "Criponi-like" phenotype. We could demonstrate that the severity of the Crisponi phenotype was dependent on the secretion capacity of the individually mutated CRLF1 protein and that the cold-induced sweating in the patients was associated with an increase of the plasma noradrenaline level. Furthermore, most recently, we showed increased expression of dopamin-beta-hydroxylase, the key enzyme of noradrenalin synthesis, in CRLF1-negative neurons. In the proposed project, we will investigate if also deficiency of KLHL7 leads to increased central noradrenaline synthesis. In this respect, we will employ neuronal KLHL7 negative cell lines, which are generated from human induced pluripotent stem cells. Furthermore, we will use a conditional knockout mouse model, in which Crlf1 is knocked out in neurons of the central nervous system. In this mouse model, we will investigate the consequences of CRLF1 deficiency on central noradrenalin synthesis, neuronal function and thermoregulation. This project will serve not only to establish a novel animal model of disordered thermoregulation, but also to identify new therapeutic targets to treat Crisponi syndrome.