Identification and characterisation of causal molecules for Crohn's disease and ulcerative colitis

克罗恩病和溃疡性结肠炎致病分子的鉴定和表征

• 批准号: MR/L000261/1
• 负责人: Tony Segal
• 金额: $ 113.17万
• 依托单位: University College London
• 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%2FL000261%2F1
• 关键词: Identification; characterisation; causal; molecules; Crohn

Summary Crohn's disease (CD) and ulcerative colitis (UC) are the two major inflammatory bowel diseases. Both conditions occur in about 1 in 1000 of the population and have a major impact on those affected. Up to 75% of CD and 25% of UC patients will require surgery at least once, and both conditions are associated with a significantly increased incidence of gastrointestinal cancer.Because they generally start in the second decade of life, and are usually lifelong conditions, they have a major detrimental effect on the social, professional and economic life of the affected individual. Direct costs of these diseases to the NHS are approximately 1 billion pounds per year. The methods used to achieve a diagnosis of these conditions are imprecise, and largely descriptive. They consist of X-rays, colonoscopy, and as a more recent development, an imaging capsule can be swallowed. Small bits of the lining of the bowel can be removed for histological examination, which produces a subjective assessment of the microscopic appearance. The development of new molecular technologies has created the possibility of identifying the basic mechanisms causing these diseases, and the molecules responsible, which could lead to more accurate diagnosis and the development of more effective treatment.We have established that:These two diseases are very different. CD is an immunodeficiency in which the patient's early inflammatory response to bacteria entering the tissues is ineffectual, leading to defective removal of bacteria from the tissues, resulting in chronic inflammation. By contrast, inflammation in UC is abnormally strong. CD affects the large and small bowel and the inflammation penetrates deep into the tissues whereas UC is confined to the superficial lining of the large bowel.In CD the macrophage, a conductor of the immunological orchestra, is defective in a large proportion of patients leading to impaired inflammation. To identify the reason for this we collected macrophages from patients and healthy control subjects and found several genes to be expressed at abnormally low levels in patients. So far we have tested two of these, ADAMDEC1, an enzyme that chops up proteins, and Optineurin, a linker molecule that is involved in moving proteins inside cells. We developed fish and mice that were lacking either ADAMDEC1 or Optineurin in order to investigate their role in bowel inflammation, and the absence of either gene caused an increased inflammation in the bowels of the animals, consistent with the effect observed in patients.We applied a similar approach to investigating the cause of UC. In this case we examined the pattern of expression of genes in the lining of the bowel, because of prior research indicating that this lining was abnormally friable in these patients. We discovered two genes that were translated at abnormally low levels in significant numbers of patients. One, Claudin 8, is involved in holding the lining cells together, and virtually nothing is known about the other, FAM5C. We wish to perform a similar study on bowel samples from patients with UC from Iceland, where the disease is very common and there is a small gene pool.We will characterise these four proteins in order to better understand their function and to determine how they predispose to the development of IBD. We would also like to investigate some of the other strong candidate genes that we have identified. IBD associated molecules might be very useful in molecular diagnostic tests.Finally we will attempt to correct the expression of target genes in either the macrophage or bowel by using drugs and/or gene replacement therapy, with the hope of identifying targeted IBD therapies.Our research programme is designed to identify and characterise molecules and mechanism responsible for the development of IBD, which will lead to improved diagnosis and treatment of these conditions.

克罗恩病（CD）和溃疡性结肠炎（UC）是两种主要的炎症性肠病。这两种情况发生在约千分之一的人口中，并对受影响的人产生重大影响。高达75%的CD患者和25%的UC患者至少需要手术一次，这两种疾病都与胃肠道癌的发病率显著增加有关，因为它们通常在生命的第二个十年开始，并且通常是终身疾病，它们对受影响个体的社会，职业和经济生活产生重大不利影响。这些疾病对NHS的直接成本每年约为10亿英镑。用于诊断这些疾病的方法不精确，主要是描述性的。它们包括X射线，结肠镜检查，以及作为最近的发展，可以吞咽的成像胶囊。小肠内壁的小块可以被切除进行组织学检查，这会产生对显微镜外观的主观评估。新的分子技术的发展为确定导致这些疾病的基本机制和相关分子创造了可能性，这可能导致更准确的诊断和更有效的治疗方法的发展。我们已经确定：这两种疾病非常不同。CD是一种免疫缺陷，其中患者对进入组织的细菌的早期炎症反应是无效的，导致细菌从组织中的去除缺陷，从而导致慢性炎症。相比之下，UC的炎症异常强烈。CD影响大肠和小肠，炎症渗透到组织深处，而UC仅限于大肠的浅表内层。在CD中，巨噬细胞是免疫乐团的指挥者，在大部分患者中存在缺陷，导致炎症受损。为了确定其原因，我们收集了患者和健康对照受试者的巨噬细胞，发现患者中有几种基因以异常低的水平表达。到目前为止，我们已经测试了其中的两种，ADAMDEC 1，一种切割蛋白质的酶，以及Optineurin，一种参与细胞内蛋白质移动的连接分子。我们培养了缺乏ADAMDEC 1或Optineurin的鱼和小鼠，以研究它们在肠道炎症中的作用，缺乏任何一种基因都会导致动物肠道炎症增加，这与在患者中观察到的效果一致。在这种情况下，我们检查了肠道衬里基因表达的模式，因为先前的研究表明，这种衬里在这些患者中异常脆弱。我们发现两个基因在大量患者中以异常低的水平翻译。其中一个，Claudin 8，参与将衬里细胞保持在一起，而另一个，FAM 5C几乎一无所知。我们希望对来自冰岛的UC患者的肠道样本进行类似的研究，该疾病非常常见，并且有一个小的基因库。我们将对这四种蛋白质进行测序，以便更好地了解它们的功能并确定它们如何使IBD易于发展。我们还想研究我们已经确定的其他一些强有力的候选基因。IBD相关分子可能在分子诊断测试中非常有用。最后，我们将尝试通过使用药物和/或基因替代疗法来纠正靶基因在巨噬细胞或肠道中的表达，以期确定IBD的靶向治疗。我们的研究计划旨在鉴定和阐明负责IBD发展的分子和机制，这将导致对这些病症的诊断和治疗的改进。

项目成果

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.

• DOI: 10.1053/j.gastro.2016.06.045
• 发表时间: 2016-10
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Chuang LS;Villaverde N;Hui KY;Mortha A;Rahman A;Levine AP;Haritunians T;Evelyn Ng SM;Zhang W;Hsu NY;Facey JA;Luong T;Fernandez-Hernandez H;Li D;Rivas M;Schiff ER;Gusev A;Schumm LP;Bowen BM;Sharma Y;Ning K;Remark R;Gnjatic S;Legnani P;George J;Sands BE;Stempak JM;Datta LW;Lipka S;Katz S;Cheifetz AS;Barzilai N;Pontikos N;Abraham C;Dubinsky MJ;Targan S;Taylor K;Rotter JI;Scherl EJ;Desnick RJ;Abreu MT;Zhao H;Atzmon G;Pe'er I;Kugathasan S;Hakonarson H;McCauley JL;Lencz T;Darvasi A;Plagnol V;Silverberg MS;Muise AM;Brant SR;Daly MJ;Segal AW;Duerr RH;Merad M;McGovern DP;Peter I;Cho JH
• 通讯作者: Cho JH

Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.

• DOI: 10.1016/j.medj.2021.04.013
• 发表时间: 2021-07-09
• 期刊: Med (New York, N.Y.)
• 作者: Matei DE;Menon M;Alber DG;Smith AM;Nedjat-Shokouhi B;Fasano A;Magill L;Duhlin A;Bitoun S;Gleizes A;Hacein-Bey-Abina S;Manson JJ;Rosser EC;ABIRISK Consortium;Klein N;Blair PA;Mauri C
• 通讯作者: Mauri C

Combinatorial Conflicting Homozygosity (CCH) analysis enables the rapid identification of shared genomic regions in the presence of multiple phenocopies.

• DOI: 10.1186/s12864-015-1360-4
• 发表时间: 2015-03-10
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Levine AP;Connor TM;Oygar DD;Neild GH;Segal AW;Maxwell PH;Gale DP
• 通讯作者: Gale DP

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

• DOI: 10.1126/scitranslmed.aai7795
• 发表时间: 2018-01-10
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Hui KY;Fernandez-Hernandez H;Hu J;Schaffner A;Pankratz N;Hsu NY;Chuang LS;Carmi S;Villaverde N;Li X;Rivas M;Levine AP;Bao X;Labrias PR;Haritunians T;Ruane D;Gettler K;Chen E;Li D;Schiff ER;Pontikos N;Barzilai N;Brant SR;Bressman S;Cheifetz AS;Clark LN;Daly MJ;Desnick RJ;Duerr RH;Katz S;Lencz T;Myers RH;Ostrer H;Ozelius L;Payami H;Peter Y;Rioux JD;Segal AW;Scott WK;Silverberg MS;Vance JM;Ubarretxena-Belandia I;Foroud T;Atzmon G;Pe'er I;Ioannou Y;McGovern DPB;Yue Z;Schadt EE;Cho JH;Peter I
• 通讯作者: Peter I

Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families.

• DOI: 10.1053/j.gastro.2016.06.040
• 发表时间: 2016-10
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Levine AP;Pontikos N;Schiff ER;Jostins L;Speed D;NIDDK Inflammatory Bowel Disease Genetics Consortium;Lovat LB;Barrett JC;Grasberger H;Plagnol V;Segal AW
• 通讯作者: Segal AW