Establishing an immune mechanome

建立免疫机制

• 批准号: 10713208
• 负责人: Meenal Datta
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713208
• 关键词: Affect; Animal Model; Antigens; Artificial Intelligence; Behavior; Biophysics; Cell Communication; Cells; Disease; Disease Progression; Engineering; Future; Generations; Genetically Engineered Mouse; Image; Immune; Immune response; Immunocompetent; Immunologics; Immunology; Inflammatory Response; Knowledge; Laboratories; Length; Mechanics; Mediating; National Institute of General Medical Sciences; Organ; Pathologic; Phenotype; Physiological; Research; Research Personnel; Science; Site; System; Testing; Tissues; Transgenic Organisms; Translational Research; cell behavior; cell motility; cellular engineering; human disease; immunogenic; in vivo; insight; mechanical force; mechanical properties; mechanical signal; multiphoton microscopy; programs; response; single-cell RNA sequencing; therapy resistant; tool; trafficking; wound

ABSTRACT Mechanical forces are often modulated in diseased or wounded tissues as a result of inflammatory responses driven by immune cell activity in the affected site(s). In fact, aberrant mechanical force generation in pathological settings may mediate disease progression and treatment resistance. However, little is known about the response of immune cells to these mechanical forces, particularly at the tissue-length scale, and even in normal physiological settings. Thus there is a critically unmet need to fill overlooked gaps in our basic understanding of the interplay between tissue-level mechanical forces and immune cell behavior, both collectively and at the single-cell level. With the support of the NIGMS R35 MIRA for Early Stage Investigators over the next five years, my laboratory will establish the first immune mechanome. We will investigate the impact of tissue mechanical forces on the phenotype and function of innate and adaptive immune cells in a variety of organs. Leveraging engineering-based tools and approaches, we will couple unbiased omics platforms to mechanical testing at multiple scales (e.g., on cells in vivo, tissues ex vivo, and organs in vivo) in order to relate immune response to mechanical forces. During multiscale compression, the trafficking, distribution, motility, cell-cell interactions, and functional behavior of immune cells will be examined and perturbed via: i) intravital and dynamic imaging (e.g., with multiphoton microscopy of fluorescent cells or genetically engineered mouse models); ii) immunocompetent, transgenic, and immunogenic animal models (e.g., OT-I/OT-II antigen systems); and iii) artificial intelligence- based cell state analysis (e.g., from single cell RNA sequencing). We will also explore our hypothesis that beneficial immune activity in the face of pathological conditions is suppressed by heightened tissue mechanical forces. Importantly, the proposed Projects are to be performed in non-specific contexts that are independent of tissue type, organ, or disease in order to maximize the potential for broad impact in the biomedical sciences. The knowledge generated will lay the groundwork for future mechanistic and translational research in both healthy and diseased settings. By operating at the interface of mechanical engineering and immunology in the burgeoning field of “mechano-immunology,” my research program is uniquely suited to reveal new biophysical insights and pathophysiological targets for human disease.

摘要 由于炎症反应，在患病或受伤的组织中，机械力经常被调节 由受影响部位的免疫细胞活性驱动。事实上，病理性的异常机械力的产生 环境可能介导疾病进展和治疗抗性。然而，人们对反应知之甚少 免疫细胞对这些机械力的反应，特别是在组织长度尺度上，甚至在正常的 生理环境因此，在我们对人类的基本认识方面， 组织水平的机械力和免疫细胞行为之间的相互作用，无论是集体还是在 单细胞水平。在未来五年内，在NIGMS R35 MIRA的早期研究人员的支持下， 我的实验室将建立第一个免疫机械组我们将研究组织机械的影响 力的表型和功能的先天性和适应性免疫细胞在各种器官。利用 基于工程的工具和方法，我们将无偏见的组学平台耦合到机械测试， 多尺度（例如，在体内细胞、离体组织和体内器官上），以便将免疫应答与 机械力在多尺度压缩过程中，运输、分布、运动、细胞-细胞相互作用和 免疫细胞的功能行为将通过以下方式进行检查和扰动：i）活体和动态成像（例如， 用荧光细胞或遗传工程小鼠模型的多光子显微术）; ii）免疫活性， 转基因和免疫原性动物模型（例如，OT-I/OT-II抗原系统）;以及iii）人工智能- 基于小区状态分析（例如，来自单细胞RNA测序）。我们还将探讨我们的假设， 在面对病理条件时有益的免疫活性被增强的组织机械 力.重要的是，拟议的项目将在独立于 组织类型，器官或疾病，以最大限度地提高在生物医学科学中产生广泛影响的潜力。 所产生的知识将为未来的机械和转化研究奠定基础， 健康和疾病的环境。通过在机械工程和免疫学的接口上操作， 新兴领域的“机械免疫学”，我的研究计划是唯一适合揭示新的生物物理 对人类疾病的洞察力和病理生理学目标。