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GENE-NUTRIENT INTERACTIONS IN NEURAL TUBE DEFECTS

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

HENKEN, DEBORAH B.

项目受资助机构

CORNELL UNIVERSITY

项目编号

3R01HD059120-08S1

立项年度

2017

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

127929.00美元

学科

Complementary and Alternative Medicine; Congenital Structural Anomalies; Dietary Supplements; Genetics; Neurosciences; Nutrition; Pediatric; Prevention; Rare Diseases; Spina Bifida;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

STOVER, PATRICK J

参与机构

EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT

项目标书摘要：DESCRIPTION (provided by applicant): We propose to elucidate the mechanism(s) and the nutritional and genetic determinants of deoxyuridine triphosphate (dUTP) incorporation into DNA, and its role in the etiology of neural tube closure defects (NTDs). Impairments in folate- and vitamin B12 (B12)-dependent one-carbon metabolism (OCM) are associated with common pathologies, including NTDs. Recently, we discovered that impaired folate-dependent de novo thymidylate (dTMP) biosynthesis causes NTDs in mice by generating serine hydroxymethytransferase 1 (SHMT)-deficient mice. SHMT1 is the only reported folate-dependent enzyme whose disruption causes folate-responsive NTDs, which provides evidence that de novo thymidylate (dTMP) biosynthesis and uracil accumulation in DNA underlies NTDs. Recently, others discovered that the ribonucleotide reductase (RNR)- catalyzed conversion of UDP to dUDP competes with folate dependent dTDP synthesis to regulate dUTP incorporation into DNA. The experiments described herein will test the overarching hypothesis that RNR-mediated dUDP synthesis competes with folate-dependent dTDP synthesis (via de novo dTMP biosynthesis & the enzyme dTMP kinase (TMPK)) to regulate dUTP incorporation into DNA, and that this interaction underlies folate and vitamin-B12-associated NTD pathogenesis. In support of this hypothesis, preliminary data show that maternal dietary deoxyuridine (dU) rescues NTDs in folate-deficient Shmt1+/- dams, whereas dietary uridine causes NTDs in wt mice, independent of dietary folate. This proposal integrates disparate observations in the literature, including that p53, RNR, folate and vitamin B12 are associated with NTDs, into a common mechanism and pathway. The results will establish the pathway for NTDs and inform future human and population studies for the prevention of folate- and B12-associated pathologies including NTDs. Aim I. Determine if vitamin B12 deficiency impairs nuclear dTMP biosynthesis and modifies NTD incidence in wt and Shmt1+/- mice. These studies will establish the role of dietary folate and B12 in nuclear dTMP biosynthesis and NTD pathogenesis, and clarify the associated mechanisms. Aim II. Determine if TMPK modifies NTD incidence in wt and Shmt1+/- mice. These studies will confirm that that disruption of de novo dTMP biosynthesis downstream of folate and B12 metabolism causes NTDs. Aim III. Determine the role of RNR in uracil accumulation in DNA and NTD pathogenesis in mice. This aim challenges the current dogma that uracil accumulation in DNA is caused by dUTP misincorporation due to impaired dTMP synthesis. These studies will determine if p53 and RNR expression affects uracil levels in DNA and NTD incidence independent of folate, and if the Shmt1 genotype modifies these outcomes. Aim IV. Validate the genetic and metabolic mechanisms of NTD pathogenesis by dietary rescue with metabolic intermediates. We will determine the mechanism and efficacy of maternal dietary dU in preventing NTDs in Shmt1+/- mice, and the mechanism and dose of maternal dietary uridine that causes NTDs.

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  • 1.Deoxyuracil in DNA and disease: Genomic signal or managed situation?

    • 关键词：
    • DNA repair; Thymidylate; dUTPase; Folate deficiency; Neural tubedefects; Uracil in DNA;NEURAL-TUBE DEFECTS; SINGLE-STRANDED-DNA; THYMIDINE KINASE 1;FOLATE-DEFICIENCY; THYMIDYLATE SYNTHASE; FOLIC-ACID; MISMATCH REPAIR;URACIL MISINCORPORATION; DEOXYRIBONUCLEIC-ACID; MEGALOBLASTIC-ANEMIA

    Genomic instability is implicated in the etiology of several deleterious health outcomes including megaloblastic anemia, neural tube defects, and neurodegeneration. Uracil misincorporation and its repair are known to cause genomic instability by inducing DNA strand breaks leading to apoptosis, but there is emerging evidence that uracil incorporation may also result in broader modifications of gene expression, including: changes in transcriptional stalling, strand break-mediated transcriptional upregulation, and direct promoter inhibition. The factors that influence uracil levels in DNA are cytosine deamination, de novo thymidylate (dTMP) biosynthesis, salvage dTMP biosynthesis, dUTPase, and DNA repair. There is evidence that the nuclear localization of the enzymes in these pathways in mammalian cells may modify and/or control the levels of uracil accumulation into nuclear DNA. Uracil sequencing technologies demonstrate that uracil in DNA is not distributed stochastically across the genome, but instead shows patterns of enrichment. Nuclear localization of the enzymes that modify uracil in DNA may serve to change these patterns of enrichment in a tissue-specific manner, and thereby signal the genome in response to metabolic and/or nutritional state of the cell.

    ...

  • 2.Folate nutrition and blood-brain barrier dysfunction

    • 关键词：
    • FOLIC-ACID; URACIL MISINCORPORATION; PSYCHIATRIC-DISORDERS;L-METHYLFOLATE; GENOMIC DNA; DEFICIENCY; TRANSPORT; GENE;SUPPLEMENTATION; SCHIZOPHRENIA

    Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency as well as to prevent chronic disease. Disease and/or its treatment can modify fundamental biological processes including cellular nutrient accretion, stability and function in cells. These effects can be isolated to a specific diseased organ in the absence of whole-body alterations in nutrient status or biochemistry. Loss of blood-brain barrier function, which occurs in in-born errors of metabolism and in chronic disease, can cause brain-specific folate deficiency and contribute to disease co-morbidity. The role of brain folate deficiency in neuropsychiatric disorders is reviewed, as well as emerging diagnostic and nutritional strategies to identify and address brain folate deficiency in blood-brain barrier dysfunction.

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  • 3.Targeting nuclear thymidylate biosynthesis

    • 关键词：
    • Nuclear thymidylate synthesis; Antifolate; Folate-mediated one-carbonmetabolism; Sumoylation; Thymidylate synthase;SQUAMOUS-CELL CARCINOMA; BASE EXCISION-REPAIR; NEURAL-TUBE DEFECTS;DIHYDROFOLATE-REDUCTASE; DNA-DAMAGE; DIHYDROPYRIMIDINE DEHYDROGENASE;THYMIDINE-PHOSPHORYLASE; SYNTHASE GENE; 5-FLUOROURACIL SUBSTITUTION;PROTEIN EXPRESSION

    Thymidylate (dTMP) biosynthesis plays an essential and exclusive function in DNA synthesis and proper cell division, and therefore has been an attractive therapeutic target. Folate analogs, known as antifolates, and nucleotide analogs that inhibit the enzymatic action of the de novo thymidylate biosynthesis pathway and are commonly used in cancer treatment. In this review, we examine the mechanisms by which the antifolate 5-fluorouracil, as well as other dTMP synthesis inhibitors, function in cancer treatment in light of emerging evidence that dTMP synthesis occurs in the nucleus. Nuclear localization of the de novo dTMP synthesis pathway requires modification of the pathway enzymes by the small ubiquitin-like modifier (SUMO) protein. SUMOylation is required for nuclear localization of the de novo dTMP biosynthesis pathway, and disruption in the SUMO pathway inhibits cell proliferation in several cancer models. We summarize evidence that the nuclear localization of the dTMP biosynthesis pathway is a critical factor in the efficacy of antifolate-based therapies that target dTMP synthesis. (C) 2016 Elsevier Ltd. All rights reserved.

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