scholarly journals 094 Characterisation of Novel Knockout Mouse Models to Investigate the Role of B55α in the Heart

2020 ◽  
Vol 29 ◽  
pp. S79
Author(s):  
N. Sergienko ◽  
D. Donner ◽  
H. Kiriazis ◽  
J. McMullen ◽  
K. Weeks
Keyword(s):  
Mouse Models ◽  
Knockout Mouse

Inhibiting Focal Adhesion Kinase Ameliorates Cyst Development in Polycystin-1–Deficient Polycystic Kidney Disease in Animal Model

2021 ◽  
Vol 32 (9) ◽  
pp. 2159-2174
Author(s):  
Jinzhao He ◽  
Shun Zhang ◽  
Zhiwei Qiu ◽  
Xiaowei Li ◽  
Huihui Huang ◽  
...  
Keyword(s):  
Mouse Models ◽  
Focal Adhesion ◽  
Knockout Mouse ◽  
Ex Vivo ◽  
Renal Cyst ◽  
Tubular Epithelial Cells ◽  
Polycystic Kidney ◽  
Content Type ◽  
Cyst Development

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous cysts originating from renal tubules and is associated with significant tubular epithelial cell proliferation. Focal adhesion kinase (FAK) promotes tumor growth by regulating multiple proliferative pathways.MethodsWe established the forskolin (FSK)-induced three-dimensional (3D) Madin–Darby Canine Kidney cystogenesis model and 8-bromoadenosine-3`,5`-cyclic monophosphate–stimulated cyst formation in ex vivo embryonic kidney culture. Cultured human renal cyst–lining cells (OX-161) and normal tubular epithelial cells were treated with FAK inhibitors or transfected with green fluorescent protein–tagged FAK mutant plasmids for proliferation study. Furthermore, we examined the role of FAK in two transgenic ADPKD animal models, the kidney-specific Pkd1 knockout and the collecting duct–specific Pkd1 knockout mouse models.ResultsFAK activity was significantly elevated in OX-161 cells and in two ADPKD mouse models. Inhibiting FAK activity reduced cell proliferation in OX-161 cells and prevented cyst growth in ex vivo and 3D cyst models. In tissue-specific Pkd1 knockout mouse models, FAK inhibitors retarded cyst development and mitigated renal function decline. Mechanically, FSK stimulated FAK activation in tubular epithelial cells, which was blocked by a protein kinase A (PKA) inhibitor. Inhibition of FAK activation by inhibitors or transfected cells with mutant FAK constructs interrupted FSK-mediated Src activation and upregulation of ERK and mTOR pathways.ConclusionsOur study demonstrates the critical involvement of FAK in renal cyst development, suggests that FAK is a potential therapeutic target in treating patients with ADPKD, and highlights the role of FAK in cAMP-PKA–regulated proliferation.

scholarly journals Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice

2020 ◽  
Author(s):  
Jessica M Snyder ◽  
Guo Zhong ◽  
Cathryn Hogarth ◽  
Weize Huang ◽  
Traci Topping ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Mouse Models ◽  
Active Metabolite ◽  
Knockout Mouse ◽  
Inflammatory Cells ◽  
Severe Phenotype ◽  
Retinoid Homeostasis ◽  
Embryonic Lethal

AbstractAll-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Global knockout of the atRA clearing enzymes Cyp26a1 or Cyp26b1 is embryonic lethal. In adults, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, post-natal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in post-natal mammals. This hypothesis was tested by generating tamoxifen inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T-lymphocytes into the skin and hyperkeratosis/hyperplasia of the non-glandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also failed to gain weight and showed fat atrophy. There were significant changes in vitamin A homeostasis demonstrating the paramount role of Cyp26b1 in regulating retinoid homeostasis in post-natal life.

scholarly journals The Spin1 interactor, Spindoc, is dispensable for meiotic division, but essential for haploid spermatid development in mice

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xue Jiang ◽  
Xiaoli Zhu ◽  
Yu Cheng ◽  
Muhammad Azhar ◽  
Xuemei Xing ◽  
...  
Keyword(s):  
Mouse Models ◽  
Meiotic Division ◽  
Knockout Mouse ◽  
Developmental Process ◽  
Physiological Role ◽  
Germline Development ◽  
Molecular Changes ◽  
Histone Marks ◽  
Downstream Signaling

AbstractIn mammals, germline development undergoes dramatic morphological and molecular changes and is epigenetically subject to intricate yet exquisite regulation. Which epigenetic players and how they participate in the germline developmental process are not fully characterized. Spin1 is a multifunctional epigenetic protein reader that has been shown to recognize H3 “K4me3-R8me2a” histone marks, and more recently the non-canonical bivalent H3 “K4me3-K9me3/2” marks as well. As a robust Spin1-interacting cofactor, Spindoc has been identified to enhance the binding of Spin1 to its substrate histone marks, thereby modulating the downstream signaling; However, the physiological role of Spindoc in germline development is unknown. We generated two Spindoc knockout mouse models through CRISPR/Cas9 strategy, which revealed that Spindoc is specifically required for haploid spermatid development, but not essential for meiotic divisions in spermatocytes. This study unveiled a new epigenetic player that participates in haploid germline development.

Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models

2003 ◽  
Vol 24 (6) ◽  
pp. 421-430 ◽  
Author(s):  
Loredana Quadro ◽  
Leora Hamberger ◽  
Vittorio Colantuoni ◽  
Max E. Gottesman ◽  
William S. Blaner
Keyword(s):  
Vitamin A ◽  
Mouse Models ◽  
Knockout Mouse ◽  
Binding Protein ◽  
Physiological Role ◽  
Retinol Binding Protein ◽  
Vitamin A Metabolism

Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models

2003 ◽  
Vol 31 (1) ◽  
pp. 216-219 ◽  
Author(s):  
B. Viollet ◽  
F. Andreelli ◽  
S.B. Jørgensen ◽  
C. Perrin ◽  
D. Flamez ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Mouse Models ◽  
Knockout Mouse ◽  
Glycogen Synthesis ◽  
Physiological Role ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To understand better the physiological role of the catalytic AMPK subunit isoforms, we generated two knockout mouse models with the α1 (AMPKα1−/−) and α2 (AMPKα2−/−) catalytic subunit genes deleted. No defect in glucose homoeostasis was observed in AMPKα1−/− mice. On the other hand, AMPKα2−/− mice presented high plasma glucose levels and low plasma insulin concentrations in the fed period and during the glucose tolerance test. Nevertheless, in isolated AMPKα2−/− pancreatic islets, glucose-stimulated insulin secretion was not affected. Surprisingly, AMPKα2−/− mice were insulin-resistant and had reduced muscle glycogen synthesis as assessed in vivo by the hyperinsulinaemic euglycaemic clamp procedure. Reduction of insulin sensitivity and glycogen synthesis were not dependent on the lack of AMPK in skeletal muscle, since mice expressing a dominant inhibitory mutant of AMPK in skeletal muscle were not affected and since insulin-stimulated glucose transport in incubated muscles in vitro was normal in AMPKα2−/− muscles. Furthermore, AMPKα2−/− mice have a higher sympathetic tone, as shown by increased catecholamine urinary excretion. Increased adrenergic tone could explain both decreased insulin secretion and insulin resistance observed in vivo in AMPKα2−/− mice. We suggest that the α2 catalytic subunit of AMPK plays a major role as a fuel sensor by modulating the activity of the autonomous nervous system in vivo.

Investigating the role of BAFF in different mouse models of allergic asthma

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
A Lorenz ◽  
M Busse ◽  
K Dalüge ◽  
AK Behrendt ◽  
G Hansen ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Mouse Models
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