UAB Childhood Cystic Kidney Disease Core Center (UAB-CCKDCC)

执行请求摘要 UAB儿童囊性肾病体内模型资源（IVMR）的总体目标 中心（CCKDC）是使研究界能够研究驱动肾囊肿发生的机制， 促进将基础发现转化为PKD患者的临床护理。如具体目标所示， 从最初的应用程序，我们正在实现这些目标，通过生成和分发鼠标 PKD/纤毛病变突变，PKD蛋白报告细胞系和与囊性变相关的通路的生物传感器 肾脏疾病然而，对于基于多个基因的PKD患者相关大鼠模型存在额外的需求。 我们从参加PKD RRC年度会议的PKD调查人员那里收到的资源请求和反馈 研讨会和FASEB PKD夏季研究会议。大鼠PKD模型的产生不是 包括在原始提案的工作范围或预算中。因此，本附录的目的是 申请资金，使UAB IVMR能够生成PKD 1和PKD 2的患者变异模型，沿着 条件flox等位基因如果没有这种补充支持，我们将无法产生这些 模型，以满足研究界的资源要求。 大鼠PKD 1和PKD 2的突变是致命的。因此，我们建议产生等位基因， 在人类ADPKD患者中鉴定为纯合子变化，因此可能是亚型突变。的 我们正在生成的PKD 1（R3268 C）和PKD 2（L 656 W）模型将是第一个与患者相关的产品线， 建立在老鼠系统中。floxed等位基因将有助于条件删除，用于基因的时间分析。 功能和包囊形成，并将用于与PKD 1（R3268 C）和PKD 2（L 656 W）的遗传杂交 因为亚型等位基因是纯合致死的几率很小我们培育的所有新的老鼠品系 一旦通过质量控制标准，就通过PKD RRC分发。这些新型号 将为临床前药物测试、疾病机制分析提供更多机会，并将促进 肾脏生理学研究，这是非常具有挑战性的使用小鼠模型。

SUPPLEMENTAL REQUEST ABSTRACT The overall objective of the In Vivo Models Resource (IVMR) in the UAB Childhood Cystic Kidney Disease Center (CCKDC) is to enable the research community to study mechanisms driving renal cystogenesis and to facilitate the translation of basic discoveries into clinical care for PKD patients. As indicated in the specific aims from the original application, we are accomplishing these goals through the generation and distribution of mice with PKD/ciliopathy mutations, PKD protein reporter lines, and biosensors for pathways associated with cystic kidney disorders. However, there is an additional demand for PKD patient relevant rat models based on multiple resource requests and feedback we've received from PKD investigators that participated in the PKD RRC Annual Symposium and the FASEB PKD Summer Research Conference. The generation of rat PKD models was not included in the scope of work or budget of the original proposal. Thus, the purpose of this supplement is to request funds that will allow the UAB IVMR to generate patient variant models for PKD1 and PKD2, along with conditional flox alleles. In the absence of this supplemental support, we would not be able to generate these models to fulfil the resource request from the research community. Null mutations in PKD1 and PKD2 in rats are lethal. Thus, we are proposing to generate alleles that were identified as homozygous changes in human ADPKD patients and thus are likely hypomorphic mutations. The PKD1(R3268C) and PKD2(L656W) models we are generating will be the first patient relevant lines to be established in the rat system. The floxed alleles will facilitate conditional deletion for temporal analysis of gene function and cyst formation and would be utilized in genetic crosses with the PKD1(R3268C) and PKD2(L656W) in the off chance that the hypomorphic alleles are homozygous lethal. All the new rat lines we generate will be distributed through the PKD RRC as soon as they pass quality control standards. Collectively these new models will provide expanded opportunities for preclinical drug testing, analysis of disease mechanisms, and will facilitate renal physiology studies that are exceedingly challenging using the mouse models.