Multi-scale modeling of lymphatic vasculature growth and adaptation

淋巴管系统生长和适应的多尺度建模

基本信息

批准号：
10413145
负责人：
Alexander Alexeev
金额：
$ 59.39万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-12 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413145
关键词：
Acquired Immunodeficiency Syndrome Active Biological Transport Affect Alzheimer&apos s Disease American Anatomy Animal Model Antigens Area Atherosclerosis Axillary Lymph Node Dissection Benchmarking Biological Biomechanics Blood Blood Circulation Brain Drains Cells Clinical Complex Computer Models Congestive Heart Failure Coupled Data Set Dermis Development Disease Disease Progression Drainage procedure Environment Equation Event Experimental Animal Model Exposure to Extracellular Matrix Failure Feedback Fibrosis Fluid Balance Force of Gravity Funding Generations Geometry Graft Rejection Grant Growth Growth Factor Head Hindlimb Homeostasis Human Hypogravity Hypoxia Image Immune Impairment Individual Inflammation Inflammatory Inflammatory Response Injury Intercellular Fluid Intestines Leg Length Ligation Limb structure Link Lipids Liquid substance Lymphangiogenesis Lymphatic Lymphatic Diseases Lymphatic System Lymphatic function Lymphedema Maintenance Mechanics Mediating Modeling Molecular Movement Multiple Sclerosis Muscle Muscle Tonus Muscular Dystrophies Nitric Oxide Operative Surgical Procedures Organ Parkinson Disease Performance Perfusion Physiological Physiology Play Process Property Proteins Publishing Pump Rattus Research Role Route Sheep Space Flight Stream Stress Structure Structure-Activity Relationship System Tail Testing Time Tissues Validation Vascular Endothelial Growth Factor C Work angiogenesis base biological adaptation to stress biomechanical test cancer therapy career computer framework computerized tools data modeling data tools experimental study insight interstitial lipid transport lymph nodes lymphatic circulation lymphatic pump lymphatic valve lymphatic vasculature lymphatic vessel macrophage mechanical load mechanical properties model development multi-scale modeling multiphoton microscopy neglect nervous system disorder novel novel strategies novel therapeutics pressure proteostasis response shear stress time interval wound healing

项目摘要

The lymphatic vasculature provides crucial functions for the maintenance of homeostasis in a variety of tissues and organs by providing the primary route through which immune cells, large proteins, lipids, and interstitial fluid are returned to the blood circulation. This requires the movement of fluid up adverse pressure gradients, a process that is achieved primarily through the intrinsic contractility of individual contractile units known as lymphangions. Lymphatic pump failure has been implicated in a variety of disease processes including lymphedema, congestive heart failure, transplant rejection, and neurological disorders. All of these processes involve the growth and remodeling (G&R) of lymphatics as they adapt to changes directly from injury or to changes in the fluid demand placed on them. These processes are quite complex involving molecular mechanisms that adapt lymphatic function and structure across very short (seconds) and long (weeks) time scales. These changes that occur at the cellular level alter pump function of individual vessels at the tissue level, and ultimately could affect pump performance of the entire lymphatic network. Thus a multiscale model that recapitulates these changes at the cellular level, integrating both the biological and mechanical variables important to the cell response, and then predicts their impact on the entire lymphatic network will be crucial to understanding disease progression and developing new therapies to restore lymphatic function. This proposal seeks to develop such a model, through a collaborative effort of three co-PIs with complementary expertise, utilizing both experiments and novel approaches in computational modeling. This will be achieved in the following four Specific Aims: 1) Develop and characterize multiscale model of lymphangion G&R. This model will describe G&R processes at the cellular level using a constrained mixture approach of the various constituents that make of the vessel and the couple this into a lumped parameter model of long lymphangion chains. 2) Develop and characterize a computational G&R fluid-structure-interaction (FSI) model of a lymphatic valve. This model will develop an approach for capturing valve G&R processes through a coupled constrained mixture model of valve growth with a FSI model of complex fluid-valve interactions. 3) Incorporation of computational models of non-mechanically mediated growth. This aim will develop a model of lymphangion growth driven by non-mechanically mediated factors coupled into the constitutive model of mechanically mediated growth. 4) Validation of computational models with a large animal experimental model relevant to human physiology. In humans, gravity is the primary mechanical load that the lymphatic system must overcome; this load is absent in small animal models. Thus the computational models of G&R will be benchmarked against a novel ligation model of the lymphatic in the leg of a sheep. Together this work will provide a “human-scale” model of the lymphatic network that incorporates molecularly events of lymphatic G&R and predicts the impact of these events on overall lymphatic system function.

淋巴管系统为维持多种组织的体内平衡提供重要功能和器官，通过提供免疫细胞、大蛋白、脂质和间质的主要途径液体返回血液循环，这需要液体向上逆压梯度移动。主要通过单个收缩单位的内在收缩性来实现的过程，称为淋巴管泵衰竭与多种疾病过程有关，包括淋巴水肿、充血性心力衰竭、移植排斥和神经系统疾病。涉及淋巴管的生长和重塑 (G&R)，因为它们会直接适应损伤或损伤带来的变化对它们的液体需求的变化这些过程非常复杂，涉及分子。在很短（秒）和很长（周）时间内适应性淋巴功能和结构的机制这些发生在细胞水平上的变化改变了组织中各个血管的泵功能。水平，并最终可能影响整个淋巴网络的泵性能，从而形成多尺度模型。在细胞水平上概括这些变化，整合生物和机械变量对细胞反应很重要，然后预测它们对整个淋巴网络的影响对于了解疾病进展并开发新疗法以恢复淋巴功能。寻求通过三位具有互补专业知识的联合 PI 的协作努力开发这样一个模型，这将在以下四个具体目标： 1) 开发并表征淋巴管 G&R 的多尺度模型。模型将使用各种约束混合方法在细胞水平上描述 G&R 过程构成血管的成分并将其耦合到长淋巴管的集中参数模型中 2) 开发并表征计算 G&R 流体结构相互作用 (FSI) 模型该模型将开发一种通过耦合捕获瓣膜 G&R 过程的方法。瓣膜生长的约束混合模型与复杂流体-瓣膜相互作用的 FSI 模型 3)。这一目标将结合非机械介导的生长的计算模型。由耦合到本构模型中的非机械介导因素驱动的淋巴管生长模型 4）通过大型动物实验验证计算模型。与人体生理学相关的模型在人体中，重力是淋巴管的主要机械负荷。系统必须克服这种负载，因此 G&R 的计算模型将不存在这种负载。这项工作将以羊腿淋巴结扎模型为基准。提供淋巴网络的“人体规模”模型，其中包含淋巴管的分子事件 G&R 并预测这些事件对整体淋巴系统功能的影响。