Integrative analysis of multi-omic signatures and cellular function in human pancreas across developmental timeline at single-cell spatial resolution

以单细胞空间分辨率对人类胰腺跨发育时间线的多组学特征和细胞功能进行综合分析

基本信息

批准号：
10776295
负责人：
Marcela Brissova
金额：
$ 25.69万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

项目摘要

Abstract Studies of human pancreas development have begun to elucidate influences in the establishment of β cell mass and formation of islets, but genetic and environmental influences that manifest during postnatal pancreas development remain unknown. The first decade of life (termed the pediatric period for this proposal) is a dynamic time in pancreas development when two critcal processes occur: (1) β cell mass is established and (2) β cells and islets functionally mature. In addition, it is the time β cell-directed autoimmunity of type 1 diabetes (T1D) often begins. Thus, understanding the molecular and cellular processes that govern pediatric pancreas development and function is key to improving the diagnosis of children and adolescents with T1D and T2D and developing strategies to prevent, or treat the β cell dysfunction. While several ongoing initiatives including the Human Islet Research Network (HIRN) have been generating datasets from adult nondiabetic, T1D, and T2D donors, there is a major gap in deep molecular and tissue-level phenotyping of pancreata from the pediatric period. Furthermore, the contributions of vascular, immune, and other stromal cell populations and their β cell interactions, to human pediatric pancreas development are largely uncharacterized, despite their known influence on adult β cell function. Our proposal is based on our exciting single-cell multi-omic spatially-resolved pilot data that will allow us to map the context specificity of T1D and related trait GWAS signals in pancreas across cell type, age, sex, and developmental stage. Moreover, using living slice technology, we will be able to investigate cellular physiology and cell-cell communication in situ with high temporal resolution to provide an insight into processes that govern β cell maturation and establishment of healthy pancreatic architecture. The overlay of spatial, physiological, transcriptional, and chromatin data from the same organs will provide unprecedented access to define changes in molecular signatures, tissue architecture, and β cell maturation. This will not only complement phenotypic data collected from mostly adult donors in the Human Pancreas Analysis Program (HPAP), but will also generate data useful to several HIRN consortia and the broader research community. Our multidisciplinary research team with complementary expertise in pancreas and islet biology, in situ physiology, single cell genomics and epigenomics, image data analysis, statistical genetics, and machine learning devised tools and analyses to discover cell state dynamic changes across the first decade of life and define how these changes influence downstream biology from transcriptional regulation, to cellular spatial organization within the pancreas, and cellular function. If successful, these studies will provide new mechanistic insights about the functional maturation of human β cells during the critical pediatric life stages. This will likely influence the way we perceive T1D pathogenesis and lead to new therapies for diabetes and other pancreas diseases.

抽象的人胰腺发育的研究已开始阐明在建立β细胞的影响胰岛的质量和形成，但是在产后胰腺过程中表现出的遗传和环境影响发展仍然未知。生命的第一十年（该提议的小儿时期称为）是当发生两个critcal过程时，胰腺发育中的动态时间：（1）建立β细胞质量并（2）β细胞和胰岛功能成熟。另外，这是β细胞定向1型自身免疫的时间糖尿病（T1D）经常开始。这是理解控制小儿的分子和细胞过程胰腺的开发和功能是改善T1D儿童和青少年诊断的关键和T2D以及制定预防或治疗β细胞功能障碍的策略。而几项正在进行的计划包括人类胰岛研究网络（HIRN）已经从成人非糖尿病患者中生成数据集 T1D和T2D供体，胰腺的深分子和组织水平表型的差距很大。小儿期。此外，血管，免疫和其他基质细胞群的贡献及其β细胞相互作用，与人类小儿胰腺发育的发展很大程度上没有特色它们对成人β细胞功能的已知影响。我们的建议基于我们令人兴奋的单细胞多摩托通过空间分辨的飞行员数据，将使我们能够映射T1D和相关性状GWAS的上下文特异性细胞类型，年龄，性别和发育阶段的胰腺信号。而且，使用生活切片技术，我们将能够在原位研究细胞生理和细胞 - 细胞通信临时解决方案，以洞悉控制β细胞成熟和建立的过程健康的胰腺建筑。来自空间，物理，转录和染色质数据的覆盖相同的器官将提供前所未有的访问来定义分子特征的变化，组织结构和β细胞成熟。这不仅将完成大多数成人收集的表型数据人类胰腺分析计划（HPAP）中的捐助者，但也将生成对几个hirn有用的数据财团和更广泛的研究社区。我们的多学科研究团队胰腺和胰岛生物学的专业知识，原位生理学，单细胞基因组学和表观基因组学，图像数据分析，统计遗传学和机器学习设计的工具和分析以发现细胞状态动态在生命的前十年的变化并定义了这些变化如何影响下游生物学转录调节，胰腺内的细胞空间组织和细胞功能。成功的研究将提供有关人β功能成熟的新机械见解关键小儿生命阶段的细胞。这可能会影响我们感知T1D发病机理的方式并导致糖尿病和其他胰腺疾病的新疗法。