Chronic Inflammation and Type 2 Diabetes: A Multi-omics Approach

摘要 2型糖尿病(T2D)的病因可能涉及多基因、代谢和 包括饮食在内的环境因素。积累实验、流行病学和临床证据 支持慢性炎症在T2D发展中的致病作用。然而，精确的机制 这些发现的基础在很大程度上是未知的，目前有证据表明 具体的炎症途径和T2D风险尚不确定。组学技术的进步导致了 与T2D风险相关的基因和代谢物的识别，但机制和因果关系的数据 仍然非常有限。系统流行病学框架下的多组学集成可能提供新的 加强我们对疾病机制的了解的途径。系统地研究它们之间的关系 在慢性炎症和T2D之间，我建议通过利用RICH来检查三个具体目标 英国生物库资源，护士健康研究(NHS)，健康专业人员后续研究(HPFS)， 拉美裔社区健康研究/拉丁裔研究(SOL)，以及基因-组织表达项目 (GTEx)。在目标1[k99]中，我将整合来自英国生物库、NHS/HPFS、SOL和 GTEx中的转录数据以检查全身炎症之间的共同基因结构 标志物和T2D，以及慢性炎症的多基因易感性是否会增加T2D风险。同时， 我将接受T2D系统生物学和尖端高维数据分析方面的广泛培训 和生物信息学。在Aim 2[R00]中，我将整合饮食和代谢数据以检查代谢组 前瞻性研究中膳食炎症潜能与T2D风险之间的关系 NHS/HPFS和SOL。在Aim 3[R00]中，我将在嵌套病例对照中进行血浆蛋白质组学分析 NHS内部的研究，以确定炎性蛋白网络与T2D风险的关系，并作为次要研究 目的，结合目标1-3的研究结果，探索T2D相关通路在多个生物学上的共同调节 尺寸。这个项目的发现可能会提高对炎症机制的理解。 T2D的基础，并确定适合早期发现和预防的新靶点/途径。我会的 由包括JoAnn Manson博士(糖尿病流行病学家)在内的跨学科团队指导/建议， 梁黎明博士(统计组学方法论专家)，Frank Hu博士(营养流行病学家)，Dr. 彼得·克拉夫特(统计遗传学家)、齐齐斌博士(遗传流行病学家)、托维亚·利伯曼博士( 蛋白质组学)和Clary Clish博士(代谢组学专家)。优秀的培训机会和关键 这些领域的领导者将为我提供先进的知识和技能，为我成功、 作为一名独立的糖尿病流行病学家，拥有系统生物学和综合经济学方面的专业知识。 该项目与NIDDK将多组学技术整合到糖尿病研究中的目标一致。

ABSTRACT The etiology of type 2 diabetes (T2D) likely involves a complex interaction of polygenic, metabolic, and environmental factors including diet. Accumulating experimental, epidemiological, and clinical evidence supports a pathogenic role of chronic inflammation in T2D development. However, the precise mechanisms underlying these findings are largely unknown, and current evidence on the causal relationships between specific inflammatory pathways and T2D risk is inconclusive. Advances in omics technologies have led to the identification of genes and metabolites associated with T2D risk, but data on mechanisms and causality are still very limited. Multi-omics integration in the framework of systems epidemiology may provide new avenues to enhance our understanding of disease mechanisms. To systematically investigate the relation between chronic inflammation and T2D, I propose to examine 3 Specific Aims by leveraging the rich resources in the UK Biobank, Nurses’ Health Studies (NHS), Health Professional Follow-up Study (HPFS), Hispanic Community Health Study/Study of Latinos (SOL), and Genotype-Tissue Expression project (GTEx). In Aim 1 [K99], I will integrate existing genomic data from the UK Biobank, NHS/HPFS, SOL, and transcriptomic data in the GTEx to examine shared genetic architectures between systemic inflammatory markers and T2D and whether polygenic susceptibility to chronic inflammation confers T2D risk. Meanwhile, I will receive extensive training in T2D systems biology and cutting-edge high-dimensional data analytics and bioinformatics. In Aim 2 [R00], I will integrate dietary and metabolomic data to examine metabolomic profiles mediating the association between dietary inflammatory potentials and T2D risk in the prospective NHS/HPFS and the SOL. In Aim 3 [R00], I will conduct plasma proteomic profiling in a nested case-control study within the NHS to identify inflammatory protein networks in relation to T2D risk, and as a Secondary Aim, integrate findings from Aim 1-3 to explore T2D-related pathways co-regulating at multiple biological dimensions. Findings from this project may improve the understanding of inflammatory mechanisms underlying T2D and identify novel targets/pathways suitable for early detection and prevention. I will be mentored/advised by an interdisciplinary team that includes Dr. JoAnn Manson (diabetes epidemiologist), Dr. Liming Liang (expert in statistical omics methodologies), Dr. Frank Hu (nutritional epidemiologist), Dr. Peter Kraft, (statistical geneticist), Dr. Qibin Qi (genetic epidemiologist), Dr. Towia Libermann (expert in proteomics), and Dr. Clary Clish (expert in metabolomics). The outstanding training opportunities with key leaders in these areas will provide me advanced knowledge and skills, positioning me for a successful, independent career as a diabetes epidemiologist with expertise in systems biology and integrated-omics. This project aligns with the NIDDK’s goal of integrating multi-omics technologies into diabetes research.