Genetic predictors of calprotectin response with anti-TNF and anti-integrin therapy in inflammatory bowel diseases

炎症性肠病中抗 TNF 和抗整合素治疗钙卫蛋白反应的遗传预测因子

基本信息

项目摘要

Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediate diseases that affect an estimated 1.5 million Americans and account for 1.5 million in direct healthcare costs. Due to their young age of onset and protracted course characterized by relapses, hospitalizations, and surgery, they exert a considerable toll on patients and society. Therapeutic advances with the availability of monoclonal antibodies against tumor necrosis factor α (anti- TNF) and anti-integrin (vedolizumab) therapies have made achievement of durable clinical and endoscopic remission increasingly possible. However, one-fifth of patients fail to achieve even an initial response and a similar proportion response annually. At present, choice of therapy is largely non-selective with sequential trial of agents from different therapeutic classes without a priori prediction of likelihood of response. However, this results in protracted morbidity due to inadequate treatment of disease and increases likelihood of permanent bowel damage in addition to exposing patients to ineffective but potentially toxic agents. Thus, there is an important unmet need for tools to predict response to each individual therapeutic class. Clinical factors such as smoking, duration of disease, location and behavior of involvement, have proved inconsistent in predicting response to therapy. In our previous work, we developed a prediction tool using genetic risk alleles to identify primary and secondary non-responders to anti-TNF therapy. This tool demonstrated both the utility of genetics and superiority of it as a predictor compared to clinical data. However, limitations to that work include retrospective adjudication of treatment response categories and reliance on improvement of symptoms which correlate poorly with endoscopic severity of inflammation, arguably a more robust marker. In this proposal, we aim to validate our prediction tool in an independent prospective cohort of patients initiating anti-TNF therapy, and important to assess its utility in determining response based on change and normalization of fecal calprotectin, a sensitive objective marker of intestinal inflammation. In addition, with the goal of developing tools to aid in personalized precise therapy by identifying mechanisms of action most likely to be of benefit to each patient, we will examine the predictive value of our existing therapy response tool in a prospective cohort of patients on treatment with vedolizumab. If our existing model is unable to predict response to vedolizumab, we will develop a separate predictive model with distinct polymorphisms to predict response to this therapeutic class. Importantly, the insights from this proposal will serve as a foundation for development of a comprehensive predictive model that also incorporates composition and metagenomic function of the gut microbiome that will significantly further our aim of providing personalized, precise care to our patients and ensuring optimal outcomes. This grant will also provide important preliminary data in support of the applicants future independent R01 funding proposal, and is a critically important step in the long-term academic success of the applicant.
克罗恩病(CD)和溃疡性结肠炎(UC)是慢性免疫介导的疾病, 估计有150万美国人受到影响,直接医疗费用为150万美元。 由于其发病年龄小,病程长,易复发, 住院和手术,它们对病人和社会造成了相当大的损失。治疗 肿瘤坏死因子α单克隆抗体的研究进展 TNF)和抗整联蛋白(Vedolizumab)疗法已经实现了持久的临床和免疫治疗。 内镜缓解越来越可能。然而,五分之一的患者甚至无法实现 一个初步的答复和类似比例的答复每年。目前,治疗的选择是 在很大程度上是非选择性的,对不同治疗类别的药物进行序贯试验, 响应可能性的先验预测。然而,这导致长期发病, 疾病治疗不充分,并增加了永久性肠损伤的可能性, 除了使患者暴露于无效但可能有毒的药剂之外。因此, 对预测对每种治疗类别的反应的工具的重要未满足的需求。临床 吸烟、病程、发病部位和行为等因素, 在预测治疗反应方面并不一致。在我们以前的工作中,我们开发了一个 使用遗传风险等位基因的预测工具,以识别原发性和继发性无应答者, 抗TNF治疗。这一工具既证明了遗传学的实用性,也证明了它作为一种 与临床数据比较。然而,这项工作的局限性包括追溯 治疗反应类别的判定和对症状改善的依赖, 与内镜下炎症严重程度相关性较差,可以说是一个更可靠的标志物。在这 我们的目标是在一个独立的前瞻性患者队列中验证我们的预测工具 开始抗TNF治疗,重要的是评估其在确定反应的基础上, 粪便钙卫蛋白的变化和正常化,一个敏感的客观标志物,肠道 炎症此外,为了开发有助于个性化精确治疗的工具, 通过确定最可能对每个患者有益的作用机制,我们将研究 我们现有的治疗反应工具在前瞻性患者队列中的预测价值, Vedolizumab治疗。如果我们现有的模型无法预测Vedolizumab的应答, 我们将开发一种具有不同多态性的单独预测模型, 这堂治疗课重要的是,该提案的见解将作为以下方面的基础: 开发一个综合预测模型,该模型还包括组成和 肠道微生物组的宏基因组功能,这将大大促进我们的目标, 为我们的患者提供个性化、精准的护理,确保最佳结果。这笔赠款还将 提供重要的初步数据,以支持申请人未来的独立R01资金 这是申请人长期学术成功的关键一步。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Ashwin N Ananthakrishnan其他文献

Su1023 Restoration of Intestinal Continuity Following Fecal Diversion for Perianal Crohn's Disease
  • DOI:
    10.1016/s0016-5085(13)61391-8
  • 发表时间:
    2013-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jenny Sauk;Deanna D Nguyen;Vijay Yajnik;Ashwin N Ananthakrishnan
  • 通讯作者:
    Ashwin N Ananthakrishnan
Prevention and interception trials in inflammatory bowel disease: an international taskforce assessment on clinical trial design
炎症性肠病的预防和拦截试验:关于临床试验设计的国际工作队评估
  • DOI:
    10.1016/s2468-1253(24)00439-4
  • 发表时间:
    2025-06-01
  • 期刊:
  • 影响因子:
    38.600
  • 作者:
    Sailish Honap;Nelly Agrinier;Joana Torres;Kenneth Croitoru;Sun-Ho Lee;Williams Turpin;Ryan C Ungaro;Manasi Agrawal;Inga Peter;Dan Turner;Iris Dotan;Ailsa L Hart;Patrick Netter;Geert D'Haens;David T Rubin;Siew C Ng;Richard Gearry;Vipul Jairath;Ashwin N Ananthakrishnan;Silvio Danese;Laurent Peyrin-Biroulet
  • 通讯作者:
    Laurent Peyrin-Biroulet

Ashwin N Ananthakrishnan的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Ashwin N Ananthakrishnan', 18)}}的其他基金

Determinants of inception of inflammation in inflammatory bowel diseases
炎症性肠病炎症发生的决定因素
  • 批准号:
    10626110
  • 财政年份:
    2021
  • 资助金额:
    $ 8.55万
  • 项目类别:
Determinants of inception of inflammation in inflammatory bowel diseases
炎症性肠病炎症发生的决定因素
  • 批准号:
    10474628
  • 财政年份:
    2021
  • 资助金额:
    $ 8.55万
  • 项目类别:
Determinants of inception of inflammation in inflammatory bowel diseases
炎症性肠病炎症发生的决定因素
  • 批准号:
    10297457
  • 财政年份:
    2021
  • 资助金额:
    $ 8.55万
  • 项目类别:
Differential impact of smoking on the transcriptome and epigenome in Crohn's disease and ulcerative colitis"
吸烟对克罗恩病和溃疡性结肠炎转录组和表观基因组的差异影响"
  • 批准号:
    10263320
  • 财政年份:
    2020
  • 资助金额:
    $ 8.55万
  • 项目类别:
Genetic predictors of anti-TNF treatment response and infections in IBD
IBD 抗 TNF 治疗反应和感染的遗传预测因子
  • 批准号:
    8676787
  • 财政年份:
    2012
  • 资助金额:
    $ 8.55万
  • 项目类别:
Genetic predictors of anti-TNF treatment response and infections in IBD
IBD 抗 TNF 治疗反应和感染的遗传预测因子
  • 批准号:
    8545840
  • 财政年份:
    2012
  • 资助金额:
    $ 8.55万
  • 项目类别:
Genetic predictors of anti-TNF treatment response and infections in IBD
IBD 抗 TNF 治疗反应和感染的遗传预测因子
  • 批准号:
    9070599
  • 财政年份:
    2012
  • 资助金额:
    $ 8.55万
  • 项目类别:
Genetic predictors of anti-TNF treatment response and infections in IBD
IBD 抗 TNF 治疗反应和感染的遗传预测因子
  • 批准号:
    8423995
  • 财政年份:
    2012
  • 资助金额:
    $ 8.55万
  • 项目类别:

相似海外基金

Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
  • 批准号:
    2335802
  • 财政年份:
    2024
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
  • 批准号:
    2335801
  • 财政年份:
    2024
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Standard Grant
A Longitudinal Study of the Relationship between Participation in a Comprehensive Exercise Program and Academic Achievement
参加综合锻炼计划与学业成绩之间关系的纵向研究
  • 批准号:
    24K14615
  • 财政年份:
    2024
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Collaborative Research: Characterizing Best Practices of Instructors who Have Narrowed Performance Gaps in Undergraduate Student Achievement in Introductory STEM Courses
合作研究:缩小本科生 STEM 入门课程成绩差距的讲师的最佳实践
  • 批准号:
    2420369
  • 财政年份:
    2024
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Standard Grant
Collaborative Research: Using Adaptive Lessons to Enhance Motivation, Cognitive Engagement, And Achievement Through Equitable Classroom Preparation
协作研究:通过公平的课堂准备,利用适应性课程来增强动机、认知参与和成就
  • 批准号:
    2335800
  • 财政年份:
    2024
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Standard Grant
WTG: Diffusion of Research on Supporting Mathematics Achievement for Youth with Disabilities through Twitter Translational Visual Abstracts
WTG:通过 Twitter 翻译视觉摘要传播支持残疾青少年数学成就的研究
  • 批准号:
    2244734
  • 财政年份:
    2023
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Standard Grant
The Impact of Emotional Experiences of Pride on Long-Term Goal Achievement Behaviors in Elite Athletes
骄傲的情感体验对优秀运动员长期目标实现行为的影响
  • 批准号:
    23K16740
  • 财政年份:
    2023
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Meta-Analysis of the Instructional-Relational Model of Student Engagement and Math Achievement: A Moderation and Mediation Approach
学生参与度和数学成绩的教学关系模型的元分析:一种调节和中介方法
  • 批准号:
    2300738
  • 财政年份:
    2023
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Standard Grant
Improving maths achievement in children with speech, language, and communication needs through 'collaborative vocabulary teaching'
通过“协作词汇教学”提高有言语、语言和交流需求的儿童的数学成绩
  • 批准号:
    2890475
  • 财政年份:
    2023
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Studentship
HSI Institutional Transformation Project: Retention and Achievement for Introductory STEM English Learners (RAISE)
HSI 机构转型项目:STEM 英语入门学习者的保留和成就 (RAISE)
  • 批准号:
    2225178
  • 财政年份:
    2023
  • 资助金额:
    $ 8.55万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了