Targeting resitin and RELM-beta to treat pulmonary hypertension

描述（由申请方提供）：肺动脉高压（PAH）是一种复杂的多因素疾病，临床结局较差。该疾病的进展的特征在于肺血管重塑、肺动脉压力增加和右心衰竭。我们的研究小组已经研究了PAH中的蛋白质家族，并证明了促炎和增殖作用，它们在啮齿动物模型中诱导PAH的能力，以及两种人类相关蛋白在人类PAH肺和外周血中上调，与PAH的血流动力学变化的严重程度相关，这表明了潜在的病因学以及生物标志物特性。在啮齿类动物中抑制该途径可预防缺氧诱导的PAH的发生。我们建议开发并启动特异性药物的临床前试验，通过抑制两种人抵抗素家族亚型：抵抗素和抵抗素样分子β（Resistin-like molecule beta，RCMP）的作用来抑制人类PAH的发作或进展。我们建议（1）通过单克隆抗体靶向靶向CIMn和CIMp，（2）通过siRNA抑制其表达，（3）高通量筛选小抑制分子，以用作改变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，并通过使用人细胞的体外模型验证其对人类治疗的适用性。我们预期，单独或与其他方法联合使用，成功的治疗可能会延迟甚至阻止疾病进展，从而使患者受益匪浅。相关性（参见说明）：肺动脉高压（PAH）是一种复杂的多因素疾病，临床结局较差，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PAH治疗方法

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