Biomarkers for the Detection of Lymphatic Vascular Insufficiency

用于检测淋巴血管功能不全的生物标志物

• 批准号: 7825655
• 负责人: Stanley G Rockson
• 金额: $ 50万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825655
• 关键词: Address; Area; Biological; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Blood; Blood Vessels; Cardiac; Chronic; Clinical; Collection; Coupled; Cutaneous; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Marker; Disease model; Early identification; Etiology; Event; Fright; Frustration; Functional disorder; Gene Targeting; Genes; Human; In Vitro; Individual; Investigation; Lead; Leg; Limb structure; Lymphatic; Lymphedema; Measures; Microarray Analysis; Modeling; Molecular; Molecular Target; Monitor; Mus; Normal tissue morphology; Pathology; Pathway interactions; Patients; Pattern; Proteins; Punch Biopsy; Regional Disease; Respiratory System; Respiratory tract structure; Risk; Sensitivity and Specificity; Serological; Serum; Skin; Source; Specificity; Stratification; Swelling; Techniques; Technology; Testing; Therapeutic; Upper arm; Validation; Work; base; candidate identification; clinically relevant; cohort; design; genome-wide; high risk; human disease; insight; instrument; public health relevance; response; serological marker; tool

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Acquired lymphatic vascular dysfunction (lymphedema) is a common, chronic, debilitating disease that is frequently under-recognized or misdiagnosed, and many patients never receive treatment. The inability to accurately predict high- risk individuals is a source of fear and frustration among patients. Previous work in a murine model of this disease has shown remarkable histological similarity to human acquired lymphedema. Utilizing genome-wide transcriptional profiling of lymphedema mouse skin, we have identified a relatively restricted list of genes and biological pathways. By analogy, genome- wide transcriptional profiling of human cutaneous, disease-specific expression patterns should lead to focused cellular and molecular insights. Paired microarray of diseased and normal tissue in the same individual will be used to identify candidate serological biomarkers. Human skin will be obtained through punch biopsy of diseased and normal limbs in individuals with unilateral acquired lymphedema; sera will be banked for subsequent assay. Paired analysis will identify significantly upregulated, target genes that encode easily measured secreted proteins with plausible relationship to lymphedema-relevant biological pathways. A multi-marker serological assay for these proteins will be developed and prospectively validated in cohorts of disease-positive and -negative subjects. This study is proposed to lead to the methodical development of a multi-marker serological bioassay with a high degree of utility and specificity for acquired lymphedema. An important investigational and clinical instrument will result, with its capacity to facilitate diagnosis, risk stratification, and monitoring of therapeutic responsiveness in patients with acquired lymphatic vascular insufficiency. Acquired lymphedema causes chronic swelling of the limb(s) that is frequently under-recognized or misdiagnosed: treatment delays are common, and many patients never receive treatment. The current investigation is designed to undertake a targeted molecular approach that will predictably lead to the development of accurate, non-invasive, serum-based testing for lymphedema. The availability of this clinical tool should predictably enhance both diagnosis and treatment. PUBLIC HEALTH RELEVANCE: Acquired lymphedema causes chronic swelling of the limb(s) that is frequently under-recognized or misdiagnosed: treatment delays are common, and many patients never receive treatment. The current investigation is designed to undertake a targeted molecular approach that will predictably lead to the development of accurate, non-invasive, serum-based testing for lymphedema. The availability of this clinical tool should predictably enhance both diagnosis and treatment.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (03) 生物标志物发现和验证以及具体挑战主题，03-HL-101：识别和验证血液、血管、心脏的诊断和治疗反应的临床相关、可量化的生物标志物和呼吸道功能障碍。获得性淋巴血管功能障碍（淋巴水肿）是一种常见的、慢性的、使人衰弱的疾病，经常被低估或误诊，许多患者从未接受过治疗。无法准确预测高风险个体是患者恐惧和沮丧的根源。先前对该疾病的小鼠模型的研究显示出与人类获得性淋巴水肿显着的组织学相似性。利用淋巴水肿小鼠皮肤的全基因组转录谱，我们确定了相对有限的基因和生物途径列表。通过类比，人类皮肤疾病特异性表达模式的全基因组转录谱应该会带来集中的细胞和分子见解。同一个体中患病组织和正常组织的配对微阵列将用于识别候选血清学生物标志物。通过对单侧获得性淋巴水肿患者的患病肢体和正常肢体进行穿刺活检来获取人体皮肤；血清将被储存以供后续测定。配对分析将鉴定显着上调的靶基因，这些基因编码易于测量的分泌蛋白，与淋巴水肿相关的生物途径有合理的关系。将开发针对这些蛋白质的多标记血清学检测方法，并在疾病阳性和阴性受试者队列中进行前瞻性验证。这项研究旨在系统地开发多标记血清学生物测定法，该测定法对于获得性淋巴水肿具有高度的实用性和特异性。将产生一种重要的研究和临床工具，其能够促进获得性淋巴血管功能不全患者的诊断、风险分层和治疗反应监测。获得性淋巴水肿会导致肢体慢性肿胀，而这种肿胀经常被忽视或误诊：治疗延误很常见，许多患者从未接受治疗。目前的研究旨在采取一种有针对性的分子方法，预计将导致开发出准确的、非侵入性的、基于血清的淋巴水肿检测方法。可以预见的是，这种临床工具的可用性应该会增强诊断和治疗。 公共卫生相关性：获得性淋巴水肿会导致肢体慢性肿胀，而这种肿胀经常被低估或误诊：治疗延误很常见，许多患者从未接受治疗。目前的研究旨在采取一种有针对性的分子方法，预计将导致开发出准确、非侵入性、基于血清的淋巴水肿检测方法。 可以预见的是，这种临床工具的可用性应该会增强诊断和治疗。