ROLES OF NEURONAL FUNCTION IN CRANIOFACIAL DEVELOPMENT

神经系统在头面部发育中的作用仍然存在 有争议的。一组有趣的证据表明，神经系统 对颅面发育很重要。临床上，患有 遗传性溶酶体储存疾病通常表现为生长发育障碍、骨骼 畸形、颅面畸形和智力低下。 组织病理学：脑、三叉神经节和脊神经节的神经元 显示肿胀的空泡状核周，储存有过多的复合体 大分子。巨型铀矿的伴生形成和伴生 突触似乎与神经元的发生和发展有关 神经元储存功能障碍通过改变电学特性和 修改躯体树突触输入的整合操作。基于 在这些观察中，申请人假设正常的神经功能是 头面部发育所需的，以及神经元功能障碍或丢失 溶酶体蓄积性疾病是导致颅面畸形的原因 发展。为了解决这一假设，申请者将雇用一只动物 严重颅面骨发育不良、生长迟缓、面部畸形模型 与粘多糖过度储存的神经元相关的畸形 和GM2神经节苷脂，由于缺乏B-己糖氨酸酶(HexA/LheB双 基因敲除小鼠)。研究人员建议恢复B-氨基己糖苷酶 将避免神经元功能障碍，并防止 颅面畸形的发展。调查人员提议 确定正常颅面是否需要神经功能 通过有条件地恢复B-氨基己糖苷酶活性来发育这些小鼠 在关键发育时期的神经元中。这些结果还将 建立关键的发育窗口，在此期间基因治疗可以 有效地应用于遗传性溶酶体储存的治疗 精神错乱。

The role of the nervous system in craniofacial development remains controversial. An interesting body of evidence suggests that the nervous system is important in craniofacial development. Clinically, patients suffering from inherited lysosomal storage diseases often exhibit growth impairment, skeletal abnormalities, craniofacial malformations, and mental retardation. Histopathologically, neurons of the brain, trigeminal and spinal root ganglia display swollen vacuolated perikarya stored with excessive amounts of complex macromolecules. The associated formation of meganeurites and collateral synapses appears responsible for the onset and progression of neuronal dysfunction in neuronal storage disorders by altering electrical properties and modifying integrative operations of somatodendritic synaptic inputs. Based on these observations, the applicant hypothesizes that normal neuronal function is required for craniofacial development, and the neuronal dysfunction or loss seen in lysosomal storage diseases is responsible for aberrant craniofacial development. To address this hypothesis, the applicants will employ an animal model with severe craniofacial dysostosis, growth retardation and facial dysmorphism, associated with excessive neuronal storage of mucopolysaccharides and GM2 gangliosides due to lack of B-hexosaminidase (hexA / lhexB double knockout mice). The investigator proposes that restitution of B-hexosaminidase in the neurons of these mice will avert neuronal dysfunction and prevent the development of craniofacial malformations. The investigators propose to determine whether neuronal function is required for normal craniofacial development in these mice by conditionally restoring B-hexosaminidase activity in neurons during critical development periods. These results would also establish the critical developmental window during which gene therapy can effectively be employed in the treatment of inherited lysosomal storage disorders.