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

针对果糖激酶、内源性果糖产生和嘌呤降解来预防和治疗遗传性果糖不耐受

• 批准号: 9891049
• 负责人: Miguel Angel Lanaspa Garcia
• 金额: $ 23.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891049
• 关键词: AMP Deaminase; Abdominal Pain; Acute; Aldehyde Reductase; Aldolase B; Allopurinol; Award; Cessation of life; Child; Chronic; Clinical; Data; Deposition; Development; Diarrhea; Diet; Dietary intake; Disease; Eating; Enzymes; Exclusion; Exposure to; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Fructokinases; Fructose; Future; Generations; Genes; Glucose; Glyceraldehyde; Growth; Hereditary fructose intolerance syndrome; Human; Hyperactive behavior; Hyperuricemia; Hypoglycemia; Impairment; Individual; Ingestion; Injury; Intake; Intestinal Neoplasms; Intoxication; Knockout Mice; Liver; Liver Failure; Measures; Metabolism; Methods; Molecular; Mus; Mutation; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Pharmacology; Phenotype; Population; Prevention; Prevention approach; Production; Publishing; Purines; Reaction; Research Personnel; Role; Scientist; Serum; Societies; Sorbitol; Source; Sucrose; Symptoms; Therapeutic; Time; Uric Acid; Vomiting; Xanthine Oxidase; autosomal recessive trait; base; clinical application; clinically relevant; fructose-1-phosphate; inorganic phosphate; insight; interest; intestinal injury; liver inflammation; liver injury; novel; polyol; prevent; programs; public health relevance; response; skills; sugar; xanthine oxidase inhibitor

 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.

 描述（由适用提供）：含糖的饮食摄入含糖的饮食在我们的社会中大大增加了，其中六分之一的人口吃了25％或更多的饮食。尽管现在建议减少减少糖摄入量的尝试，但在当今文化中很难避免暴露于HFC和蔗糖。一组遭受添加糖的宽度使用的组是遗传性果糖不耐症的个体（HFI），这是一种常染色体隐性隐性，其受试者在果糖摄入后受试者会出现严重的反应，腹部疼痛，腹部疼痛，呕吐，腹泻，有症状性低血糖，低血糖，高乳液，高尿素，甚至在儿童中。果糖代谢是由两种酶引发的，果糖酶使果糖酶磷酸糖酶从果糖1-磷酸果实中，导致ATP部署和尿酸的产生，以及醛糖酶B，并进一步将果糖1-磷酸分子分解为HFI，从而导致Aldolase B的突变导致菌株的突变，从而导致酸性酶的繁殖，并导致菌根的突变，均匀地促进了菌根型，并导致菌根的产生，并将其施用。果糖摄入比正常个体中观察到的要大得多。我们在醛糖酶B缺乏小鼠中的初步数据表明，暴露于饮食中或内源性产生的果糖时，其缺乏与果糖激酶的过度激活，生长迟钝，严重的低血糖，肝/肠损伤和死亡有关，这些损伤和死亡被抑制时完全阻塞。有趣的是，当小鼠高尿液血症表明尿酸在HFI发病机理中的重要有害作用时，在醛固酶B缺乏小鼠中观察到的有害作用会加剧。这些观察结果使我们得出了总体假设，即果糖代谢对果糖1-磷酸盐的封锁可预防藻酶B缺乏受试者中的HFI。具体而言，我们建议1）藻酶B缺乏症的果糖基因敲除小鼠在暴露于果糖后不会发展HFI，2）通过抑制藻酶还原和多元途径在临床上相关的内源性果糖产生的阻断。 对于患有醛酶B缺乏症和3）降低尿酸产生和积累的人是预防和治疗HFI的重要治疗方法。本应用中提出的研究在临床上具有相关性，因为它们将为未来的疗法（靶向果糖酶，降低醛糖酶减少，AMP脱氨酶和/或氧化氧化物）提供见解，在我们的社会中，唯一的治疗方法（避免果糖）几乎是不可能的。申请人将与包括DRS在内的一大批合作者进行数。迪恩·托兰（Dean Tolan） - 临床遗传性果糖intlerance-和理查德·约翰逊（Richard Johnson）的世界专家 - 糖和果糖代谢领域的著名科学家。该奖项将使申请人担任早期研究员（ESI），可以发展必要的技能，并通过两种教学计划并支持与不同部门的各种研究人员进行互动，并通过两种教义计划来完全成为独立的科学家的财务需求。