Mechanisms underlying developmental programming of lifelong health

终身健康发展规划的潜在机制

• 批准号: MR/L007215/1
• 负责人: Jason Wolf
• 金额: $ 67.16万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL007215%2F1
• 关键词: Mechanisms; underlying; developmental; programming; lifelong

Obesity and related disorders, including type 2 diabetes and cardiovascular disease, are major health problems in the UK and many other parts of the world. Over 20% of UK adults were classed as obese in 2004 and this will reach over 50% by 2050 unless current trends can be halted. Obesity-related problems were estimated to cost the NHS around £1bn in 2007 and this is predicted to rise to almost £10bn by 2050. The true financial and societal costs are much greater. These metabolic health problems are generally attributed to the direct effects on individuals of poor "Western" diets and insufficient exercise. However, it has also become clear that poor metabolic health can be reinforced from one generation to the next. This is because during life in the womb and as suckling infants, the critical growth periods of early life, babies experience an environment that is heavily influenced by the health status and habits of their mother. In particular, a mother's diet (as well as factors such as smoking and alcohol consumption), maternal obesity and gestational diabetes can have life-long effects on the health of her offspring. In other words, while we are used to the idea that "you are what you eat", we should also pay attention to the idea that "you are what your mother ate".Our research aims to find out how factors affecting growth during early life, particularly poor maternal diet, can influence health during adult life. It is thought that developing offspring are "programmed" by the environment they experience in a process that involves switching on and off genes that control processes such as growth, adipose tissue development and also the way the body stores and uses energy. We aim to identify the key genes in offspring that are affected by developmental programming. To do this we are studying mice in which one gene, called Grb10, is disrupted. These mice are large at birth and have favourable metabolic health characteristics during adult life, including low adipose levels and an enhanced ability to use glucose after a meal. The fact that this gene links early growth with adult health makes it a strong candidate as one of the genes involved in metabolic programming. We will test if this is true essentially by finding out whether the "anti-diabetic" profile of these mice can protect them from the adverse health effects of a poor maternal diet. We will also use these mice to reveal other genes switched on or off as part of the programming process. By identifying the genes involved in developmental programming, and finding out when and in which parts of the body their activity is altered, we will identify new ways to improve human health in the future. This could include the development of tests to identify people at increased risk of common health problems in later life, improvements in dietary advice or dietary supplementation during pregnancy, or the development of drugs that alter the activity of developmental programming genes.

肥胖和相关疾病，包括2型糖尿病和心血管疾病，是英国和世界上许多其他地方的主要健康问题。2004年，超过20%的英国成年人被列为肥胖，如果目前的趋势不能停止，到2050年，这一比例将超过50%。据估计，2007年，与肥胖相关的问题花费了NHS大约10亿英镑，预计到2050年，这一数字将上升到近100亿英镑。真正的经济和社会成本要高得多。这些代谢健康问题通常归因于不良的“西方”饮食和缺乏锻炼对个人的直接影响。然而，也很清楚的是，不良的代谢健康可能会一代一代地加剧。这是因为，在子宫内和哺乳婴儿时期，即早期生命的关键成长时期，婴儿所处的环境受到母亲健康状况和习惯的严重影响。特别是，母亲的饮食（以及吸烟和饮酒等因素）、母亲肥胖和妊娠期糖尿病可能对其后代的健康产生终生影响。换句话说，当我们习惯了“你吃什么就是什么”的观念时，我们也应该注意“你妈妈吃什么就是你什么”的观念。我们的研究旨在找出影响早期生长的因素，特别是母亲的不良饮食，如何影响成年后的健康。据认为，发育中的后代是由他们所经历的环境“编程”的，这一过程包括打开和关闭控制生长、脂肪组织发育以及身体储存和使用能量方式等过程的基因。我们的目标是确定受发育程序影响的后代的关键基因。为了做到这一点，我们正在研究一种名为Grb10的基因被破坏的老鼠。这些小鼠出生时体型较大，成年后具有良好的代谢健康特征，包括低脂肪水平和饭后使用葡萄糖的能力增强。事实上，这种基因将早期生长与成人健康联系起来，这使它成为参与代谢程序的基因之一。我们将通过发现这些小鼠的“抗糖尿病”特征是否能保护它们免受母亲不良饮食对健康的不利影响来检验这是否属实。我们还将用这些老鼠来揭示作为编程过程一部分的其他基因的开启或关闭。通过识别参与发育程序的基因，并找出它们的活动何时以及在身体的哪个部分发生改变，我们将在未来找到改善人类健康的新方法。这可能包括开发检测方法，以确定晚年出现常见健康问题的风险增加的人群，改进怀孕期间的饮食建议或膳食补充，或开发改变发育编程基因活动的药物。

项目成果

Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes.

• DOI: 10.1186/s12915-014-0099-8
• 发表时间: 2014-12-31
• 期刊: BMC biology
• 影响因子: 5.4
• 作者: Madon-Simon M;Cowley M;Garfield AS;Moorwood K;Bauer SR;Ward A
• 通讯作者: Ward A

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

评估低剂量暴露于环境中化学混合物的致癌潜力：未来的挑战。

• DOI: 10.1093/carcin/bgv039
• 发表时间: 2015-06
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Goodson WH 3rd;Lowe L;Carpenter DO;Gilbertson M;Manaf Ali A;Lopez de Cerain Salsamendi A;Lasfar A;Carnero A;Azqueta A;Amedei A;Charles AK;Collins AR;Ward A;Salzberg AC;Colacci A;Olsen AK;Berg A;Barclay BJ;Zhou BP;Blanco-Aparicio C;Baglole CJ;Dong C;Mondello C;Hsu CW;Naus CC;Yedjou C;Curran CS;Laird DW;Koch DC;Carlin DJ;Felsher DW;Roy D;Brown DG;Ratovitski E;Ryan EP;Corsini E;Rojas E;Moon EY;Laconi E;Marongiu F;Al-Mulla F;Chiaradonna F;Darroudi F;Martin FL;Van Schooten FJ;Goldberg GS;Wagemaker G;Nangami GN;Calaf GM;Williams G;Wolf GT;Koppen G;Brunborg G;Lyerly HK;Krishnan H;Ab Hamid H;Yasaei H;Sone H;Kondoh H;Salem HK;Hsu HY;Park HH;Koturbash I;Miousse IR;Scovassi AI;Klaunig JE;Vondráček J;Raju J;Roman J;Wise JP Sr;Whitfield JR;Woodrick J;Christopher JA;Ochieng J;Martinez-Leal JF;Weisz J;Kravchenko J;Sun J;Prudhomme KR;Narayanan KB;Cohen-Solal KA;Moorwood K;Gonzalez L;Soucek L;Jian L;D'Abronzo LS;Lin LT;Li L;Gulliver L;McCawley LJ;Memeo L;Vermeulen L;Leyns L;Zhang L;Valverde M;Khatami M;Romano MF;Chapellier M;Williams MA;Wade M;Manjili MH;Lleonart ME;Xia M;Gonzalez MJ;Karamouzis MV;Kirsch-Volders M;Vaccari M;Kuemmerle NB;Singh N;Cruickshanks N;Kleinstreuer N;van Larebeke N;Ahmed N;Ogunkua O;Krishnakumar PK;Vadgama P;Marignani PA;Ghosh PM;Ostrosky-Wegman P;Thompson PA;Dent P;Heneberg P;Darbre P;Sing Leung P;Nangia-Makker P;Cheng QS;Robey RB;Al-Temaimi R;Roy R;Andrade-Vieira R;Sinha RK;Mehta R;Vento R;Di Fiore R;Ponce-Cusi R;Dornetshuber-Fleiss R;Nahta R;Castellino RC;Palorini R;Abd Hamid R;Langie SA;Eltom SE;Brooks SA;Ryeom S;Wise SS;Bay SN;Harris SA;Papagerakis S;Romano S;Pavanello S;Eriksson S;Forte S;Casey SC;Luanpitpong S;Lee TJ;Otsuki T;Chen T;Massfelder T;Sanderson T;Guarnieri T;Hultman T;Dormoy V;Odero-Marah V;Sabbisetti V;Maguer-Satta V;Rathmell WK;Engström W;Decker WK;Bisson WH;Rojanasakul Y;Luqmani Y;Chen Z;Hu Z
• 通讯作者: Hu Z

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

• DOI: 10.1371/journal.pbio.1002315
• 发表时间: 2015-12
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Hurst LD;Ghanbarian AT;Forrest AR;FANTOM consortium;Huminiecki L
• 通讯作者: Huminiecki L

Neighboring Genes Show Correlated Evolution in Gene Expression.

• DOI: 10.1093/molbev/msv053
• 发表时间: 2015-07
• 期刊: Molecular biology and evolution
• 影响因子: 10.7
• 作者: Ghanbarian AT;Hurst LD
• 通讯作者: Hurst LD

Impulsive Choice in Mice Lacking Paternal Expression of Grb10 Suggests Intragenomic Conflict in Behavior.

• DOI: 10.1534/genetics.118.300898
• 发表时间: 2018-05
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Dent CL;Humby T;Lewis K;Ward A;Fischer-Colbrie R;Wilkinson LS;Wilkins JF;Isles AR
• 通讯作者: Isles AR