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

摘要 UAB儿童囊性肾脏病中心活体模型资源(IVMR)的总体目标 (CCKDC)是为了促进对推动肾脏囊变的机制的研究，这将加速翻译 将基本发现转化为PKD患者的临床护理。IVMR正在通过以下方式实现这一目标 相关通路的PKD相关动物模型和生物传感器的产生、应用和分布 患有囊性肾病。如原始应用程序中所述，IVMR正在生成并可用 向PKD联盟提供多只小鼠、斑马鱼和大鼠的PKD模型。然而，根据反馈和 应PKD研究领域的科学家的要求，有必要提供未包括在内的额外资源 在最初的提案中。因此，在没有这一补充请求的情况下，我们将无法生成这些 新的模型系统。这包括： 1)小鼠胚胎干细胞和人诱导多能干细胞(IPSCs)，其中自我标记 标签被整合到PKD蛋白中，随后可以通过基因改造来表达 与患者相关的变种，以生成小鼠模型并用于有机化合物研究。 2)一系列基于新技术的小鼠cAMP生物传感器，可以检测cAMP水平的变化 在纤毛或胞质中起始。 3)新的小鼠模型，允许合成配体诱导胞浆或纤毛产生cAMP 目的：探讨cAMP信号在包囊发育中的作用。 通过本行政补充提供的资源将通过以下方式生成和分配 一旦他们可用，PKD联盟就会立即进行。他们将为PKD研究人员提供新的机会 可视化活体样本中的PKD蛋白，包括活体中的活体肾脏，以测试患者变异是如何改变的 蛋白质稳定性、转运、定位、相互作用、膜插入等。cAMP生物传感器将促进 细胞内cAMP浓度与原发纤毛和包囊变化关系的研究 发展。最后，营地诱导系统将解决一个关键问题，即营地是否起源于 从纤毛或胞浆中排出的物质在包囊形成过程中起着重要作用。总体而言，由此产生的新的研究机会 将加快对肾囊肿形成的细胞和分子基础的研究步伐， 将有助于集中策略治疗这种疾病，并将成为临床前测试的新模型的基础。

ABSTRACT The overall objective of the In Vivo Models Resource (IVMR) in the UAB Childhood Cystic Kidney Disease Center (CCKDC) is to facilitate research into the mechanisms driving renal cystogenesis that will accelerate translation of basic discoveries into clinical care for PKD patients. The IVMR is accomplishing this objective through the generation, application, and distribution of PKD relevant animal models and biosensors for pathways associated with cystic kidney disease. As described in the original application, the IVMR is generating and making available to the PKD Consortium multiple mouse, zebrafish, and rat models for PKD. However, based on feedback and requests from scientists in the PKD research field, there is a need for additional resources that are not included in the original proposal. Thus, in the absence of this supplemental request, we will not be able to generate these new model systems. This includes: 1) Mouse embryonic stem cells and human induced pluripotent stem cells (iPSCs) wherein self-labeling tags are incorporated into the PKD proteins and can be subsequently genetically modified to express patient relevant variants to generate the mouse models and use in organoid studies. 2) A series of mouse cAMP biosensors based on new technology that can detect changes in cAMP levels initiated in either the cilium or cytosol. 3) New mouse models that will allow synthetic ligand induced cAMP production in either the cytosol or cilia to evaluate cAMP signaling during cyst development. The resources made available through this administrative supplement will be generated and distributed through the PKD Consortium as soon as they are available. They will provide new opportunities for PKD researchers to visualize the PKD proteins in live samples, including in vivo in live kidneys, to test how patient variants alter protein stability, transport, localization, interactions, membrane insertion, etc. The cAMP biosensors will facilitate research into where cAMP concentrations change in the cell in relation to the primary cilium and during cyst development. Finally, the cAMP induction system will address a critical question of whether cAMP originating from the cilium or cytosol is important in cyst formation. Collectively, the new research opportunities resulting from the resources will advance the pace of research into the cellular and molecular basis of renal cyst formation, will help focus stratigies to treat the disease, and will be the basis for new models for preclinical testing.