Targeting fructokinase, endogenous fructose production and purine degradation for the prevention and treatment of hereditary fructose intolerance

 描述（由申请人提供）：在我们的社会中，含果糖的糖的膳食摄入量急剧增加，六分之一的人口食用其饮食的25%或更多。虽然现在建议尝试减少糖的摄入量，但在今天的文化中，很难避免接触HFCS和蔗糖。广泛使用添加糖的一个群体是患有遗传性果糖不耐受（HFI）的个体，HFI是一种常染色体隐性遗传，其受试者在摄入果糖后发生严重反应，包括腹痛、呕吐、腹泻、症状性低血糖、高尿酸血症，甚至儿童死亡。果糖代谢由两种酶启动，果糖激酶将果糖磷酸化为果糖-1-磷酸，导致ATP消耗和尿酸生成，而醛缩酶B将果糖-1-磷酸分子进一步分解为磷酸二氢丙酮和甘油醛。HFI是由醛缩酶B的突变引起的，导致果糖-1-磷酸的积累，显著的ATP消耗和果糖摄入后尿酸的产生，其比在正常个体中观察到的要大得多。我们在醛缩酶B缺陷小鼠中的初步数据表明，在暴露于果糖时-在饮食中或内源性产生-，其缺陷与果糖激酶过度活化、生长迟缓、严重低血糖、肝/肠损伤和死亡相关，当果糖激酶被抑制时，这些损伤和死亡被完全阻断。值得注意的是，当小鼠高尿酸血症时，在醛缩酶B缺陷小鼠中观察到的有害作用加剧，表明尿酸在HFI发病机制中的重要有害作用。这些观察结果使我们得出了我们的总体假设，即阻断果糖代谢为果糖-1-磷酸可保护醛缩酶B缺乏的受试者免受HFI。具体而言，我们提出1）果糖激酶敲除小鼠与醛缩酶B缺乏不会发展HFI后暴露于果糖，2）通过抑制醛糖还原酶和多元醇途径阻断内源性果糖生产是临床相关的 对于患有醛缩酶B缺乏症的人，以及3）降低尿酸产生和积累是预防和治疗HFI的重要治疗方法。本申请中提出的研究具有临床相关性，因为它们将为这种疾病的未来疗法（靶向果糖激酶、醛糖还原酶、AMP脱氨酶和/或黄嘌呤氧化酶）提供见解，在这种疾病中，唯一的治疗（避免果糖）在我们的社会中几乎是不可能的。申请人将与包括Dean Tolan博士在内的优秀合作者团队一起计数-临床遗传性果糖不耐受的世界专家-和Richard约翰逊-糖和果糖代谢领域的着名科学家-。该奖项将允许申请人作为早期研究者（ESI）发展必要的技能和财务需求，以完全成为一名独立的科学家，并将通过教学计划和促进与不同部门的各种研究人员的互动来提供智力发展。

 DESCRIPTION (provided by applicant): Dietary intake of sugars containing fructose has dramatically increased in our society with one-sixth of the population eating 25% of their diet or more. While attempts to reduce sugar intake are now recommended, it is very difficult to avoid exposure to HFCS and sucrose in today's culture. One group that suffers from the widespread use of added sugars are individuals with Hereditary Fructose Intolerance (HFI), an autosomal recessive whose subjects develop severe reactions following fructose ingestion, with abdominal pain, vomiting, diarrhea, symptomatic hypoglycemia, hyperuricemia, and even death in children. Fructose metabolism is initiated by two enzymes, fructokinase that phosphorylates fructose to fructose-1- phosphate causing ATP depletion and uric acid generation, and aldolase b that further splits the fructose-1- phosphate molecule into dihydroacetone phosphate and glyceraldehyde. HFI is caused by the mutation in aldolase B leading to accumulation of fructose-1-phosphate, marked ATP depletion and uric acid generation following fructose ingestion that is much greater than that observed in normal individuals. Our preliminary data in aldolase b deficient mice suggest that upon exposure to fructose -in diet or endogenously produced-, its deficiency is associated with fructokinase hyperactivation, growth retardation, severe hypoglycemia, liver/intestinal injury and death which are completely blocked when fructokinase is inhibited. Of interest, the deleterious effects observed in aldolase b deficient mice are exacerbated when mice are hyperuricemic suggesting an important deleterious role of uric acid in the pathogenesis of HFI. These observation led us to our overall hypothesis that the blockade of fructose metabolism to fructose-1- phosphate protects against HFI in subjects with aldolase b deficiency. Specifically, we propose that 1) fructokinase knockout mice with aldolase b deficiency will not develop HFI upon exposure to fructose, 2) the blockade of endogenous fructose production by inhibition of aldose reductase and the polyol pathway is clinically relevant for people with aldolase b deficiency and 3) lowering uric acid production and accumulation is an important therapeutic approach in the prevention and treatment of HFI. The studies proposed in this application are clinically relevant as they will provide insights into future therapies (targeting fructokinase, aldose reductase, AMP deaminase and/or xanthine oxidase) for this disease in which the only treatment (avoidance of fructose) has become almost impossible in our society. The applicant will count with an excellent group of collaborators that include Drs. Dean Tolan -a world expert in clinical hereditary fructose intolerance- and Richard Johnson -a renowned scientist in the field of sugar and fructose metabolism-. This award will allow the applicant as an early stage investigator (ESI) to develop the skills necessary and the financial needs to fully become an independent scientist and will provide for intellectual development through both didactic programs and by facilitating interactions with a variety of researchers in different departments.