A Canine Model for Human X-Linked Ectodermal Dysplasia

描述（由申请人提供）： 我的学术兴趣涉及胎儿发育，疾病机制和人类遗传疾病的动物模型的相互关联的领域。 自从获得兽医学位以来，我一直在学术环境中工作，担任研究型临床医生。我完成了兽医医学遗传学的实习，然后获得了博士学位。在人类遗传性疾病（粘多糖样变性VII型）的小鼠模型中研究子宫内移植。 在开始担任助理教授之前，我接受了进一步的鼠造血训练。我进一步指导研究培训的直接目标是扩大我在细胞和分子生物学领域的知识。通过额外的专业培训，对本资助申请中提出的模型的进一步研究以及对我在过去几个月中发现的另外三种遗传性皮肤病模型的表征，我希望提交RO 1资助申请。我的住院医师，研究生和研究生培训提供了描述和发表遗传模式，疾病过程的原则和几种遗传疾病的治疗方式的机会。在过去的九年里，我已经能够建立一个具有X连锁外胚层发育不良（HED）临床，病理和遗传特征的犬群，其特征是毛发和汗腺发育不全，牙齿缺失和畸形。 与人类HED患者一样，受影响的狗患肺部疾病的风险增加，但我也发现对其他通常是良性的，很少致命的非肺部感染性疾病的易感性增加。因此，有可能狗具有与人类免疫缺陷相关的新描述的HED等同的犬，由NEMO基因缺陷引起，该基因也是X连锁的。我的假设是，HED狗有一个缺陷，在ED 1，基因负责X-连锁外胚层发育不良的人，肺部疾病是由于特定的缺陷，在局部免疫。HED犬的遗传缺陷将通过对ED 1和NEMO基因进行测序、确定突变并进行表达研究来研究，以提供原理证明并了解发育期间疾病的基础。此外，将对HED犬进行检查，以证明特异性免疫缺陷是肺部疾病的原因，而不是之前认为的呼吸道粘液腺缺乏。

DESCRIPTION (provided by applicant): My academic interests involve the inter-related areas of fetal development, mechanisms of disease, and animal models of human genetic diseases. I have worked in academic environments as a research-oriented clinician since receiving my veterinary medical degree. I completed a residency in veterinary medical genetics, then obtained a Ph.D. studying in utero transplantation in a mouse model of a human genetic disease (mucopolysaccharidosis type VII). I obtained further training in murine hematopoeisis before starting my assistant professorship. My immediate goal for further mentored research training is to expand my knowledge in the field of cell and molecular biology. With the additional specialized training, the further investigation of the model proposed in this grant application and characterization of three more models of genetic skin disorders I have found in the last several months, I expect to submit an application for an RO1 grant. My residency, graduate, and postgraduate training have provided the opportunity to characterize and publish the mode of inheritance, principles of disease processes, and treatment modalities of several genetic diseases. Over the past nine years, I have been able to establish a colony of dogs with clinical, pathologic, and genetic features of X-linked ectodermal dysplasia (HED) characterized by hypoplasia of hair and sweat glands, and missing and malformed teeth. As in human patients with HED, the affected dogs are at increased risk for pulmonary disorders, but I have also found an increased susceptibilty to other, usually benign, rarely fatal, non-pulmonary infectious diseases. Thus, there is the possibility that the dogs have the canine equivalent to the newly described HED associated with immune deficiency in humans, caused by a defect in the NEMO gene which is also X-linked. My hypothesis is that the HED dogs have a defect in ED1, the gene responsible for X-linked ectodermal dysplasia in man and that the pulmonary disorders are due to specific defects in local immunity. The genetic defect in the HED dogs will be studied by sequencing both the ED1 and the NEMO gene, determining the mutation, and performing expression studies to provide proof of principle and to understand the basis of disease during development. Furthermore, the HED dogs will be examined to demonstrate that a specific immune deficiency is responsible for pulmonary disease rather than the previously thought lack of respiratory mucoid glands.