Improving transcapillary transport by reducing interstitial fluid pressure

通过降低间质液压力改善跨毛细血管运输

基本信息

批准号：
7608616
负责人：
Leonardo Jose de Moura Carvalho
金额：
$ 9.47万
依托单位：
LA JOLLA BIOENGINEERING INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-05 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7608616
关键词：
Adhesions Antineoplastic Agents Area Basement membrane Biological Assay Biomedical Engineering Biosensor Blood Blood Vessels Blood capillaries Bone Marrow C57BL/6 Mouse CSPG4 gene Caliber Cancer Patient Catheters Cells Clinical Collagen Contracts Convection Cutaneous Melanoma Development Diagnostic Diagnostic Procedure Diffusion Discipline Drug Delivery Systems Drug Transport Elements Endothelial Cells Endothelium Etiology Exhibits Extracellular Matrix Face Fiber Gel Generations Ground Substance Hypertension In Vitro Intercellular Fluid Investigation Investments Isometric Contraction Isometric Exercise Isotonic Contraction Isotonic Exercise Kidney Knock-out Knockout Mice Label Lead Length Lifting Light Liquid substance Lymphangiogenesis Malignant Neoplasms Mammary Neoplasms Measures Mechanics Methods Modeling Molecular Weight Monoclonal Antibodies Mus Muscle Cells Myocardium NG2 antigen National Institute of Biomedical Imaging and Bioengineering Normal tissue morphology Operative Surgical Procedures Pathologic Neovascularization Peptides Pericytes Phage Display Pharmaceutical Preparations Phase Physiology Plasma Principal Investigator Property Relative (related person)Role Rubber Science Simulate Site Skeletal Muscle Smooth Muscle Stream Surface Testing Therapeutic Therapeutic Agents Tissues Tracer Transducers Transgenic Mice Transgenic Organisms Treatment outcome Water Weight Wild Type Mouse angiogenesis base cancer therapy capillary density enhanced green fluorescent protein extracellular fluid flow human tissue improved innovation interstitial malignant breast neoplasm minimally invasive nanoparticle neovascular neovascularization neovasculature novel novel diagnostics pressure progenitor programs reconstitution sensor skills stem subcutaneous tool tumor vasculogenesis

Adhesions Antineoplastic Agents Area Basement membrane Biological Assay Biomedical Engineering Biosensor Blood Blood Vessels Blood capillaries Bone Marrow C57BL/6 Mouse CSPG4 gene Caliber Cancer Patient Catheters Cells Clinical Collagen Contracts Convection Cutaneous Melanoma Development Diagnostic Diagnostic Procedure Diffusion Discipline Drug Delivery Systems Drug Transport Elements Endothelial Cells Endothelium Etiology Exhibits Extracellular Matrix Face Fiber Gel Generations Ground Substance Hypertension In Vitro Intercellular Fluid Investigation Investments Isometric Contraction Isometric Exercise Isotonic Contraction Isotonic Exercise Kidney Knock-out Knockout Mice Label Lead Length Lifting Light Liquid substance Lymphangiogenesis Malignant Neoplasms Mammary Neoplasms Measures Mechanics Methods Modeling Molecular Weight Monoclonal Antibodies Mus Muscle Cells Myocardium NG2 antigen National Institute of Biomedical Imaging and Bioengineering Normal tissue morphology Operative Surgical Procedures Pathologic Neovascularization Peptides Pericytes Phage Display Pharmaceutical Preparations Phase Physiology Plasma Principal Investigator Property Relative (related person)Role Rubber Science Simulate Site Skeletal Muscle Smooth Muscle Stream Surface Testing Therapeutic Therapeutic Agents Tissues Tracer Transducers Transgenic Mice Transgenic Organisms Treatment outcome Water Weight Wild Type Mouse angiogenesis base cancer therapy capillary density enhanced green fluorescent protein extracellular fluid flow human tissue improved innovation interstitial malignant breast neoplasm minimally invasive nanoparticle neovascular neovascularization neovasculature novel novel diagnostics pressure progenitor programs reconstitution sensor skills stem subcutaneous tool tumor vasculogenesis

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项目摘要

DESCRIPTION (provided by applicant): This is a resubmission of an R03 application to National Institute of Biomedical Imaging and Bioengineering (NIBIB). We have recently developed a minimally invasive, biosensor-based, diagnostic surgical procedure for measuring interstitial fluid pressure (IFP) in cancer. We propose to apply this new diagnostic technique to elucidate the role of contractile pericytes in IFP and transcapillary transport of nanoparticles in tumors. Similar to isometric contraction of skeletal muscle, neovascular pericytes generate contractile forces not only on the vessel walls but also on interstitial fluid entrapped within extracellular fibers, referred to as tissue gel. We will test whether interstitial fluid pressure in cancer can be reduced by interfering with pericytes to improve the convection of nanoparticle based anti-cancer drugs. We will test whether inhibition of pericytes results in a decrease in interstitial fluid pressure due to decreasing compressive contractile forces elicited by pericytes. We will test whether pericyte-NG2 proteoglycan inhibition lowers IFP and improves convection from the plasma to the interstitial space. We will quantify transcapillary transport by using nanoparticles as tracers. We anticipate finding a higher transcapillary convection of nanoparticles (simulating high molecular weight anti-cancer drugs) and lower interstitial fluid pressure in breast tumors when pericytes are inhibited. By combining skills and disciplines in bioengineering, clinical physiology and microvascular sciences this project will transform our biosensor-based diagnostic procedure into a tangible diagnostic tool for cancer patients. The use of ultraminiature transducer-tipped catheters as cancer interstitial fluid pressure biosensors is innovative in light of novel use of biosensors portfolio of National Institute of Biomedical Imaging and Bioengineering. The role of compressive forces generated by pericytes within breast cancer stroma has never been investigated; which makes this proposal innovative in shedding light on the etiology of interstitial hypertension, a significant clinical problem in breast cancer therapy in terms of drug delivery.

描述（由申请人提供）：这是向国家生物医学成像与生物工程研究所（Nibib）的R03申请的重新提交。我们最近开发了一种微创的，基于生物传感器的诊断手术程序，用于测量癌症中的间质液压（IFP）。我们建议采用这种新的诊断技术来阐明收缩周细胞在IFP和肿瘤中纳米颗粒的经毛细管运输中的作用。与骨骼肌的等距收缩类似，新血管周周的周细胞不仅在容器壁上产生收缩力，而且在夹在细胞外纤维内的间隙液上，也称为组织凝胶。我们将通过干扰周细胞来改善基于纳米颗粒的抗癌药物的对流来测试癌症中的间质液压力。我们将测试周围的抑制是否会导致降低周细胞引起的压缩收缩力，导致间质流体压力降低。我们将测试周细胞NG2蛋白聚糖抑制是否会降低IFP并改善从血浆到间隙空间的对流。我们将使用纳米颗粒作为示踪剂来量化经毛细管运输。我们预计，当抑制周细胞时，纳米颗粒（模拟高分子量抗癌药物）的较高的经毛细血管对流（模拟高分子量抗癌药物）和较低的间质液压。通过结合生物工程，临床生理学和微血管科学的技能和学科，该项目将使我们的基于生物传感器的诊断程序转变为癌症患者的有形诊断工具。鉴于国家生物医学成像和生物工程研究所的生物传感器投资组合的新颖使用，将超显影剂用作癌性导管用作癌症间隙生物传感器具有创新性。从未研究过周围乳腺癌基质中周围产生的压缩力的作用。这使该提案的创新性阐明了间隙高血压的病因，这是乳腺癌治疗的重大临床问题。