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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：
10378174
负责人：
Alexander Alexeev
金额：
$ 6.62万
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/10378174
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 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 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 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 parent grant 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.

淋巴管系统对维持多种组织的内环境平衡起着至关重要的作用通过提供免疫细胞、大蛋白、脂质和间质的主要途径液体被送回血液循环。这需要流体沿不利的压力梯度向上移动，主要通过单个收缩单位的固有收缩能力实现的过程，称为淋巴管。淋巴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、移植排斥反应和神经系统疾病。所有这些过程涉及淋巴管的生长和重塑(G&R)，因为它们直接适应损伤或施加在他们身上的流体需求的变化。这些过程相当复杂，涉及分子在很短(几秒)和很长(几周)时间内适应淋巴功能和结构的机制比例。这些发生在细胞水平上的变化改变了组织中个别血管的泵功能水平，并最终可能影响泵的整个淋巴网络的性能。因此，一个多尺度模型这在细胞水平上概括了这些变化，整合了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将是至关重要的了解疾病进展并开发恢复淋巴功能的新疗法。这项建议寻求通过三个具有互补专业知识的共同私人投资机构的合作努力，开发这样一个模式，在计算建模中利用实验和新方法。这将在以下时间实现以下四个具体目标：1)建立和表征淋巴G&R的多尺度模型模型将使用受约束的混合方法在细胞级别描述G&R过程构成血管的成分和将其耦合到长淋巴管的集中参数模型中锁链。2)建立和表征了一个计算G&R流固耦合(FSI)模型淋巴瓣。该模型将开发一种方法来捕获阀门G&R过程，通过耦合阀门生长的约束混合模型和复杂流体-阀门相互作用的FSI模型。3) 纳入非机械调节生长的计算模型。这一目标将制定一种本构模型中非力学因素驱动的淋巴管生长模型机械调节的增长。4)用大型动物实验验证计算模型与人体生理学相关的模型。在人类中，重力是主要的机械负荷，淋巴系统必须克服；这种负荷在小动物模型中是不存在的。因此，G&R的计算模型将以一种新的绵羊腿部淋巴结扎模型为基准。这项工作将共同努力提供“人体尺度”的淋巴网络模型，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。