Biomarkers for the Detection of Lymphatic Vascular Insufficiency

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特定的挑战主题03-HL-101：鉴别和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可定量生物标志物。获得性淋巴管功能障碍（水肿）是一种常见的慢性衰弱性疾病，经常被低估或误诊，许多患者从未接受治疗。无法准确预测高危个体是患者恐惧和沮丧的根源。先前在这种疾病的小鼠模型中的工作已经显示出与人类获得性水肿的显著组织学相似性。利用全基因组转录谱的水肿小鼠皮肤，我们已经确定了一个相对有限的基因和生物学途径的列表。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分析应该导致集中的细胞和分子见解。将使用同一个体中患病和正常组织的配对微阵列来鉴定候选血清学生物标志物。将通过对单侧获得性水肿个体的患病和正常肢体进行穿刺活检获得人皮肤;将血清储存用于后续测定。配对分析将鉴定显著上调的靶基因，其编码易于测量的分泌蛋白，与水肿相关生物学途径具有合理的关系。将开发这些蛋白质的多标志物血清学测定，并在疾病阳性和阴性受试者队列中进行前瞻性验证。本研究旨在建立一种对获得性水肿具有高度实用性和特异性的多标志物血清学生物测定方法。一个重要的研究和临床工具将产生，其能力，以促进诊断，风险分层，并监测治疗反应性患者获得性淋巴管功能不全。获得性水肿导致肢体慢性肿胀，经常被低估或误诊：治疗延迟是常见的，许多患者从未接受治疗。目前的研究旨在进行有针对性的分子方法，可以预见的是，这将导致发展准确的，非侵入性的，基于血清的水肿检测。这种临床工具的可用性应该可以预见地提高诊断和治疗。 公共卫生相关性：获得性水肿导致肢体慢性肿胀，经常被低估或误诊：治疗延迟是常见的，许多患者从未接受治疗。目前的研究旨在进行有针对性的分子方法，可以预见的是，这将导致发展准确的，非侵入性的，基于血清的水肿检测。 这种临床工具的可用性应该可以预见地提高诊断和治疗。

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.