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

UAB 儿童囊性肾病核心中心 (UAB-CCKDCC)

• 批准号: 10455818
• 负责人: Bradley K. Yoder
• 金额: $ 20.69万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455818
• 关键词: Address; Administrative Supplement; Animal Model; Automobile Driving; Biological Models; Biosensor; Cell model; Cells; Childhood; Cilia; Communities; Concentration Camps; Cyclic AMP; Cyst; Cystic Kidney Diseases; Cystic kidney; Cytosol; Development; Disease; Engineering; Feedback; Funding; Future; Generations; Goals; Human; Kidney; Label; Ligands; Measurement; Measures; Membrane; Modeling; Molecular; Mus; Organoids; PKD2 protein; Pathogenesis; Pathway interactions; Patients; Play; Pre-Clinical Model; Preclinical Testing; Production; Proteins; Rattus; Reporter; Research; Research Personnel; Resources; Role; Sampling; Scientist; Second Messenger Systems; Series; Signal Transduction; Speed; System; Testing; Translations; Variant; Zebrafish; base; catalyst; cell type; clinical care; embryonic stem cell; homologous recombination; in vivo; in vivo Model; induced pluripotent stem cell; insight; mouse model; new technology; novel; parent grant; polycystic kidney disease 1 protein; protein function; protein kinase D; success; symposium

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.

摘要 UAB儿童囊性肾病中心体内模型资源（IVMR）的总体目标 （CCKDC）是为了促进对驱动肾囊肿发生机制的研究， PKD患者临床治疗的基础发现。IVMR正在通过以下方式实现这一目标： PKD相关动物模型和相关通路生物传感器的生成、应用和分布 患有囊性肾病。如原始申请中所述，IVMR正在生成并提供 PKD Consortium的多个PKD小鼠、斑马鱼和大鼠模型。但是，根据反馈和 根据PKD研究领域科学家的要求，需要提供未包括在内的额外资源。 在最初的提案中。因此，如果没有此补充请求，我们将无法生成这些 新模式系统这包括： 1)小鼠胚胎干细胞和人诱导多能干细胞（iPSC），其中自标记 标签被掺入PKD蛋白中，并且随后可以被遗传修饰以表达 患者相关变体以产生小鼠模型并用于类器官研究。 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 起源于纤毛或细胞质。 3)新的小鼠模型，将允许在胞质溶胶或纤毛中合成配体诱导cAMP产生 以评估囊肿发育过程中的cAMP信号传导。 通过这一行政补编提供的资源将通过下列方式产生和分配： PKD财团，一旦他们可用。它们将为PKD研究人员提供新的机会， 可视化活体样本中的PKD蛋白，包括活体肾脏中的PKD蛋白，以测试患者变体如何改变 蛋白质稳定性、运输、定位、相互作用、膜插入等。cAMP生物传感器将促进 研究cAMP浓度在细胞中与初级纤毛的关系以及在包囊期间的变化 发展最后，cAMP诱导系统将解决一个关键问题， 从纤毛或胞质溶胶中分离的蛋白质在包囊形成中是重要的。总的来说，新的研究机会 从资源将推进研究的步伐到肾囊肿形成的细胞和分子基础， 将有助于集中治疗这种疾病的策略，并将成为临床前测试新模型的基础。