Targeting resitin and RELM-beta to treat pulmonary hypertension

描述(由申请人提供)：肺动脉高压(PAH)是一种复杂的、多因素的疾病，临床结果很差。疾病进展的特点是肺血管重构、肺动脉压力升高和右心衰竭。我们的研究小组已经研究了PAH中的抵抗素蛋白家族，并在啮齿动物模型中证明了它们的促炎和增殖作用，以及它们在人类PAH肺和外周血中的上调与PAH血流动力学变化的严重程度相关，提示了潜在的病因学和生物标志物特性。在啮齿动物中抑制这一途径可以防止低氧诱导的PAH的发展。我们建议开发和启动特定药物的临床前测试，通过抑制两种人类抵抗素家族亚型：抵抗素和抵抗素样分子β(RELMP)的作用来抑制人类PAH的发生或进展。我们建议(1)用单抗靶向抵抗素和RELMp，(2)用siRNA抑制它们的表达，(3)高通量筛选小抑制分子，作为改变PAH病程的治疗方法。我们将在血管生长的小鼠模型中研究这些潜在的治疗方法，并通过使用人类细胞的体外模型来验证它们是否适合人类治疗。我们预计，成功的治疗单独或与其他方法联合使用，可以延缓甚至阻止疾病的进展，从而使患者SUN/IVAL显著受益。相关性(参见说明)：肺动脉高压(PAH)是一种复杂的、多因素的疾病，临床结果很差，我们已经发现了一种导致PAH的新途径。这项提案寻求开发针对这一途径的药物和生物标记物，以创造治疗PAH的新方法

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease with poor clinical outcome. The progress of the disease is characterized by pulmonary vascular remodelling, increases in pulmonary artery pressure, and right heart failure. Our research group has investigated the resistin family of proteins in PAH and demonstrated pro-inflammatory and proliferative actions, their ability to induce PAH in rodent models, and that the two human correlate proteins are upregulated in human PAH lung and peripheral blood in correlation with severity of hemodynamic changes of PAH, suggesting potential etiologic as well as biomarker properties. Inhibition of this pathway in rodents prevents the development of hypoxia-induced PAH. We propose to develop and initiate pre-clinical testing of specific agents to inhibit the onset or progression of PAH in humans by inhibiting the action of the two human resistin-family isoforms: Resistin and Resistin-like molecule beta (RELMP). We suggest (1) targeting resistin and RELMp by monoclonal antibodies, (2) inhibiting their expression by siRNA, and (3) High throughput screening for small inhibitory molecules to be used as therapeutic approaches to alter the course of PAH. We will investigate these potential therapies in a murine model of vascular growth and verify their suitability for human treatment through in vitro models using human cells. We anticipate that a successful treatment may, alone or in combination with other approaches, delay or even arrest disease progression, and thus significantly benefit patient sun/ival. RELEVANCE (See instructions): Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease with poor clinical outcome and we have discovered a new pathway that can cause PAH. This proposal seeks to develop drugs and biomarkers that target this pathway to create new treatments for PAH