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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.

淋巴血管系统为维持多种组织的内稳态提供了至关重要的功能