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（由申请人提供）：在我们的社会中，含果糖糖的膳食摄入量急剧增加，六分之一的人口摄入了其饮食的 25% 或更多，虽然现在建议尝试减少糖摄入量，但很难做到。在当今的文化中，避免接触高果糖玉米糖浆和蔗糖 患有遗传性果糖不耐症 (HFI)（一种常染色体遗传性果糖不耐症）的人群因广泛使用添加糖而受到影响。隐性遗传病，其受试者在摄入果糖后会出现严重反应，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。果糖代谢是由两种酶启动的，果糖激酶将果糖磷酸化为果糖-1-磷酸，导致 ATP 耗尽。和尿酸生成，醛缩酶 b 进一步分裂果糖-1-磷酸分子HFI 是由醛缩酶 B 突变引起的，导致 1-磷酸果糖的积累、明显的 ATP 消耗和果糖摄入后尿酸的产生，其数量比我们在正常个体中观察到的要多得多。醛缩酶 b 缺陷小鼠表明，在接触饮食中或内源产生的果糖后，其缺陷与果糖激酶过度激活、生长当果糖激酶受到抑制时，发育迟缓、严重低血糖、肝/肠损伤和死亡都被完全阻断。有趣的是，当小鼠尿酸过多时，在醛缩酶 b 缺陷小鼠中观察到的有害作用会加剧，这表明尿酸在糖尿病发病机制中具有重要的有害作用。 HFI。这些观察结果使我们得出总体假设，即阻断果糖代谢为 1-磷酸果糖可防止醛缩酶受试者发生 HFI。具体来说，我们建议 1) 醛缩酶 b 缺陷的果糖激酶敲除小鼠在接触果糖时不会发生 HFI，2) 通过抑制醛糖还原酶和多元醇途径来阻断内源果糖的产生具有临床相关性。 对于醛缩酶 b 缺乏症患者以及 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，因为它们将为未来的治疗提供见解（针对果糖激酶、醛糖）。还原酶、AMP脱氨酶和/或黄嘌呤氧化酶）对于这种疾病，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。一个优秀的合作者团队，其中包括临床遗传性果糖不耐受领域的世界专家 Dean Tolan 博士和糖和果糖代谢领域的著名科学家 Richard Johnson。该奖项将允许申请人作为早期研究人员。 ESI）培养完全成为一名独立科学家所需的技能和财务需求，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。