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疾病，临床预后较差。疾病进展的特点是肺血管重构、肺动脉压升高和右心衰。我们的研究小组已经研究了PAH中的抵抗素家族蛋白，并证明了它们的促炎和增殖作用，它们在啮齿动物模型中诱导PAH的能力，并且这两种人类相关蛋白在人类PAH肺和外周血中上调，与PAH血流动力学变化的严重程度相关，提示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防止缺氧诱导的多环芳烃的发展。我们建议开发和启动特异性药物的临床前试验，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)用单克隆抗体靶向抵抗素和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。我们将在小鼠血管生长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验证它们对人类治疗的适用性。我们预计，成功的治疗可以单独或与其他方法联合，延缓甚至阻止疾病进展，从而显着造福患者的太阳/竞争。相关性（见说明书）：肺动脉高压（PAH）是一种复杂的多因素疾病，临床预后较差，我们发现了一种可导致PAH的新途径。该提案旨在开发针对这一途径的药物和生物标志物，以创造新的治疗多环芳烃的方法

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