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.

淋巴脉管系统为维持多种组织的体内平衡提供了关键功能和器官通过提供主要途径，免疫细胞，大蛋白，脂质和间隙液体返回血液循环。这需要流体向不利压力梯度移动，a 主要通过称为单个收缩单元的固有收缩性来实现的过程淋巴管。在包括淋巴水肿，充血性心力衰竭，移植排斥和神经系统疾病。所有这些过程涉及淋巴机的生长和重塑（G＆R），因为它们会直接从损伤或转变为液体需求的变化对它们的变化。这些过程非常复杂，涉及分子在非常短（秒）和长（周）时间内适应淋巴功能和结构的机制秤。在细胞水平上发生的这些变化改变了组织在组织的泵功能水平，最终可能影响整个淋巴网络的泵性能。那个多尺度模型这概括了在细胞水平上的这些变化，从而整合了生物学变量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了解疾病进展并开发新疗法以恢复淋巴功能。这个建议试图通过具有完善专业知识的三个共同策划的合作努力来开发这种模型，使用计算建模中的实验和新方法。这将在以下四个具体目标：1）开发和表征淋巴管G＆R的多尺度模型。这模型将使用各种约束的混合方法在细胞水平上描述G＆R过程构成船只的组成，这对夫妻构成了长歌词的总参数模型链。 2）开发和表征A的计算G＆R流体结构相互作用（FSI）模型淋巴瓣。该模型将开发一种通过耦合捕获阀G＆R流程的方法瓣膜生长的约束混合模型与复杂流体阀相互作用的FSI模型。 3）合并非机械介导的生长的计算模型。这个目标将发展由非机械介导的因子驱动的淋巴管生长模型机械介导的生长。 4）用大动物实验的计算模型验证与人类生理相关的模型。在人类中，重力是淋巴的主要机械负荷系统必须克服；在小动物模型中，这种负载不存在。 G＆R的计算模型将基准反对绵羊腿上淋巴的新型结扎模型。这项工作将提供淋巴网络的“人尺度”模型，该模型结合了淋巴的分子事件 G＆R并预测这些事件对总体淋巴系统功能的影响。