Improved Growth Patterns in Cystic Fibrosis Mice after Loss of Histone Deacetylase 6
Improved Growth Patterns in Cystic Fibrosis Mice after Loss of Histone Deacetylase 6
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DOI：
10.1038/s41598-017-03931-2
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发表时间：
2017-06-16
影响因子：
4.6
通讯作者：
Hodges, Craig A.
中科院分区：
文献类型：
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作者：
Rymut, Sharon M.;Corey, Deborah A.;Hodges, Craig A.
囊性纤维化 (CF) 患者的生长障碍已得到充分记录，并显示与较差的疾病结果相关。这一观察结果在 CF 动物模型中也成立，包括小鼠、猪、大鼠和雪貂。生长缺陷的病因尚不清楚，我们之前的工作证明 CF 细胞模型和组织中微管蛋白乙酰化减少，可通过抑制组蛋白脱乙酰酶 6 (HDAC6) 来纠正。在这里，我们假设 HDAC6 的缺失将改善 CF 小鼠模型的生长表型。 Hdac6 敲除小鼠与 F508del (CF) 小鼠杂交产生 F508del/Hdac6 (CF/HDA) 小鼠。分析了生长、脂肪沉积、存活和生物电测量。 CF/HDA 小鼠的身长和体重有所改善，但 CFTR 功能没有得到纠正。从机制上讲，Igf1 水平可能会导致体长增加和生育能力提高。体重增加归因于脂肪沉积增加，这可能是由脂肪细胞分化增加介导的。 CF 相关的生长缺陷可以通过抑制 HDAC6 来改善，这进一步表明它是 CF 的潜在治疗靶点。
Growth failure in cystic fibrosis (CF) patients has been well-documented and shown to correlate with poorer disease outcomes. This observation is also true in CF animal models, including mouse, pig, rat, and ferret. The etiology underlying growth deficits is unknown, and our previous work demonstrated reduced tubulin acetylation in CF cell models and tissue that is correctable by inhibition of histone deacetylase-6 (HDAC6). Here, we hypothesize that loss of HDAC6 will improve growth phenotype in a CF mouse model. Hdac6 knockout mice were crossed with F508del (CF) mice to generate F508del/Hdac6 (CF/HDA) mice. Growth, fat deposits, survival, and bioelectric measurements were analyzed. CF/HDA mice displayed improvements in length and weight with no correction of CFTR function. Mechanistically, Igf1 levels likely account for increased length and improvements in fertility. Weight gain is attributed to increased fat deposits potentially mediated by increased adipocyte differentiation. CF-related growth deficits can be improved via inhibition of HDAC6, further implicating it as a potential therapeutic target for CF.