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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：
10829148
负责人：
Alexander Alexeev
金额：
$ 7.82万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10829148
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 Infiltration 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 Macrophage 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 Proliferating Property Proteins Publishing Pump Rattus Research Role Route Sheep Space Flight Stream Stress Structure Structure-Activity Relationship System Tail Testing Time Tissues VEGFC gene Validation Vascular Endothelial Growth Factor C Work angiogenesis 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 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.

淋巴管系统为维持各种组织的稳态提供了重要的功能通过提供免疫细胞、大蛋白质、脂质和间质液体返回血液循环。这需要流体沿逆压力梯度向上运动，这一过程主要通过单个收缩单位的内在收缩性来实现，淋巴管淋巴泵衰竭与多种疾病过程有关，包括水肿、充血性心力衰竭、移植排斥和神经系统疾病。所有这些过程涉及骨骼肌的生长和重塑（G&R），因为它们适应直接来自损伤或对它们的流体需求的变化。这些过程相当复杂，涉及分子适应淋巴功能和结构的机制在很短（秒）和很长（周）的时间鳞片这些发生在细胞水平的变化改变了组织中单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。多尺度模型在细胞水平上重现这些变化，整合生物学和机械学变量，重要的细胞反应，然后预测他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新的治疗方法以恢复淋巴功能。这项建议寻求通过三个具有互补专业知识的共同PI的合作努力，利用实验和计算建模中的新方法。这将在具体目标如下：1）建立和表征淋巴管G&R的多尺度模型。这模型将描述G&R过程在细胞水平上使用各种约束混合方法组成的血管和耦合成一个集总参数模型的长淋巴管店2)开发和表征计算G&R流体-结构-相互作用（FSI）模型，淋巴瓣该模型将开发一种方法，用于通过耦合捕获阀门G&R过程。阀生长的约束混合模型与复杂流体-阀相互作用的FSI模型。第三条非机械介导生长的计算模型的合并。这一目标将发展一个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机械介导的生长。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，重力是淋巴管的主要机械负荷。系统必须克服;这种负荷在小动物模型中不存在。因此，G&R的计算模型将以绵羊腿部淋巴管的新型结扎模型为基准。这项工作将提供淋巴网络的“人类规模”模型，其中包含淋巴的分子事件 G&R，并预测这些事件对整体淋巴系统功能的影响。