China
Africa
Explore chapters and articles related to this topic
Rodent Autosomal Dominant Polycystic Kidney Disease Models
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Sara J. Holditch, Raphael A. Nemenoff, Katharina Hopp
The first transgenic Pkd1 model published was the hPKD1(TPK1-3) mouse, in which a 108 kbp region containing human PKD1 and the flanking TSC2 gene were cloned from a P1-derived artificial chromosome and injected into a mouse pronucleus, resulting in the TPK1, TPK2, and TPK3 independent founder lines.139 The purpose of the model was to assess the function of human PKD1 in a mouse and evaluate the phenotypic consequence of altering PC1 levels. In respect to the former, the authors crossed Pkd1tm1Jzh;hPKD1 (Pkd1del34/+;hPKD1)1 mice with Pkd1del34/+ mice in order to see whether or not Pkd1del34/del34;hPKD1 survive. Human PKD1 was able to rescue the embryonic lethal phenotype of Pkd1del34/del34 mice, suggesting that human PC1 is functionally active in the murine setting. In respect to the latter, the authors made the surprising observation that two of the founder lines, TPK1 and TPK3, reliably presented with progressive PKD and PLD. These novel observations revealed that not only loss of PC1 but also PC1 overexpression can result in PKD/PLD pathology. Furthermore, Pkd1del34/del34;hPKD1 animals, while rescued, still presented with PKD/PLD phenotypes at adult age (5–11 m), possibly due to lower levels of the exogenous rescue hPC1 relative to basal levels of endogenous murine PC1. Both of these phenotype descriptions highlight that a delicate dosage of PC1 expression is critical to maintain renal and liver morphology. At the time, this concept was a shift in paradigm, contradicting accumulating evidence that ADPKD was recessive at the cellular level, and required a second-somatic hit (loss of the WT allele) for cyst initiation.3,140,141
Animal models of ischemic stroke and their impact on drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Dirk M. Hermann, Aurel Popa-Wagner, Christoph Kleinschnitz, Thorsten R. Doeppner
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by missense mutations altering the number of cysteine residues in the extracellular domain of the NOTCH3 gene (Notch3ECD), leading to pathological deposition of Notch3ECD at the plasma membrane and extracellular deposits called granular osmiophilic material (GOM) [96]. By knock-in and transgenic approaches using smooth muscle-specific promoters or a P1-derived artificial chromosome containing the Notch3 locus, major efforts were made for modeling CADASIL, with limited success (Table 2). Most of these mice developed two pathological hallmarks, i.e. Notch3ECD aggregates and GOM deposits in the brain, but no ischemic lesions. Rarefication of cerebral white matter microvessels was noted starting at 12 months of age, when mutant Notch3 level was increased by a factor of ≥4 in mice carrying a P1-derived artificial chromosome (TgPAC-Notch3R169C) [99]. Unlike CADASIL patients, TgPAC-Notch3R169C mice have a normal lifespan and do not exhibit lacunar brain infarcts.