Immune cells and cytokines mediating fibrodysplasia ossificans progressiva

 描述（由申请人提供）：进行性骨化性纤维发育不良（FOP）是一种无法治疗的罕见先天性疾病，可导致骨骼肌异位骨化（HO），导致固定、极度疼痛和最终死亡。FOP患者在编码骨形态发生蛋白（BMP）I型受体Alk 2的Acvr 1基因的一个拷贝中携带激活单点突变。尽管突变体Alk 2在许多组织中广泛表达，但HO病变的形成并不连续。相反，HO出现在与全身感染或肌肉挫伤相关的独特的散发性“耀斑”中。因此，临床医生和研究人员一直怀疑HO耀斑是由炎症和/或免疫细胞引发的。 使用FOP小鼠模型，该实验室和其他实验室已经表明，增加炎症会增强HO，而高剂量糖皮质激素会抑制HO。不幸的是，糖皮质激素在临床上并不有效，并且对炎症或免疫系统触发HO的机制知之甚少。TNFa是炎症部位最高表达的细胞因子，而巨噬细胞是骨骼肌损伤部位最丰富的免疫细胞。有趣的是，TNFa和巨噬细胞都已显示在某些情况下增强软骨内骨形成，表明在FOP中可能的作用。该提议将解决巨噬细胞和TNF α的内源性表达是FOP中异位骨化的关键介质的总体假设。目的1将确定内源性TNF α的作用，目的2将确定巨噬细胞在FOP小鼠模型中HO的起始和发展中的作用。这些研究的结果有可能确定新的靶点，从而导致预防或减少这种致命疾病中HO的治疗。

 DESCRIPTION (provided by applicant): Fibrodysplasia ossificans progressiva (FOP) is am untreatable rare congenital disease that results heterotopic ossification (HO) in skeletal muscle leading to immobilization, extreme pain, and eventual death. FOP patients carry an activating single point mutation in one copy of the Acvr1 gene that encodes the bone morphogenetic protein (BMP) Type I receptor, Alk2. Despite widespread expression of mutant Alk2 in numerous tissues the formation of HO lesions is not continuous. Rather, HO appears in distinct sporadic "flares" associated with systemic infections or muscle contusions. Hence, clinicians and researchers have long suspected that HO flares are initiated by inflammation and/or immune cells. Using mouse models of FOP, this laboratory and others have shown that increasing inflammation enhances HO, while high-dose glucocorticoids suppress HO. Unfortunately, glucocorticoids are not clinically effective and little is known about the mechanisms by which inflammation or the immune system trigger HO. TNFa is the most highly expressed cytokine at sites of inflammation, while macrophages are the most abundant immune cells in sites of skeletal muscle damage. Interestingly, both TNFa and macrophages have been shown to enhance endochondral bone formation in certain settings, suggesting possible roles in FOP. This proposal will address the overall hypothesis that macrophages and endogenous expression of TNFa are critical mediators of heterotopic ossification in FOP. Aim 1 will determine the role of endogenous TNFa and Aim 2 will determine the role of macrophages in the initiation and development of HO in a mouse model of FOP. The results of these studies hold to potential to identify new targets that could lead to treatments to prevent or reduce HO in this deadly disease.