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

补充请求摘要 UAB儿童囊性肾脏病体内模型资源(IVMR)的总体目标 中心(CCKDC)的目的是使研究团体能够研究促使肾脏囊变发生的机制，并 促进将基本发现转化为对PKD患者的临床护理。如具体目标所示 从最初的应用程序来看，我们正在通过MICE的生成和分布来实现这些目标 与PKD/纤毛病变突变、PKD蛋白报告系和与囊性病变相关的通路的生物传感器 肾脏疾病。然而，对于与PKD患者相关的基于多个 我们从参加PKD RRC年会的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模型的建立不是 包括在原提案的工作范围或预算中。因此，本补编的目的是 申请资金，以允许UAB IVMR为PKD1和PKD2生成患者变体模型，以及 条件FLOX等位基因。在没有这种补充支持的情况下，我们将无法产生这些 模型，以满足研究社区的资源要求。 大鼠PKD1和PKD2的零突变是致命的。因此，我们建议产生的等位基因 在人类ADPKD患者中被鉴定为纯合子变化，因此很可能是亚型突变。这个 我们正在生成的PKD1(R3268C)和PKD2(L656W)模型将是第一个与患者相关的线路 在大鼠系统中建立起来。被标记的等位基因将为基因的时序分析提供条件删除的便利 在与PKD1(R3268C)和PKD2(L656W)的遗传杂交中被利用 在亚型等位基因纯合致死的可能性很小的情况下。我们产生的所有新的老鼠系都将是 一旦通过质量控制标准，就通过PKD RRC分发。总而言之，这些新车型 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 使用小鼠模型进行极具挑战性的肾脏生理学研究。

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.