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Improving the Old, Embracing the New: Implications of Alcohol Research for Future Practice
Published in Gary Rosenberg, Weissman Andrew, Behavioral and Social Sciences in 21st Century Health Care: Contributions and Opportunities, 2021
Among the newer tools aiding alcohol scientists in their search for the genes involved in alcoholism is the use of transgenic animals. Transgenic animals are animals in which a specific gene that scientists wish to study is inserted into an animal. “Knockouts” are another type of animal model in which scientists remove or “knock out” the gene under investigation. Careful study of the animal’s biological and behavioral responses before and after genes are inserted or knocked out can give scientists information on the role of the gene under investigation. For example, when scientists eliminated or “knocked-out” the gene for the serotonin 5HT-1B receptor, mice became more aggressive and drank more alcohol. NIAAA intramural scientists have demonstrated that this gene is associated with the same behaviors in humans. Other studies in mice have found that different genes influence alcohol consumption in males and females, suggesting that different genes may also influence alcoholism in men and women. Based on this research, 16 genes have been identified which have shown a response to alcohol, and this number is growing. These transgenic and “knock-out” animal models will continue to yield important information about the genetic underpinnings of alcoholism vulnerability.
The science of biotechnology
Published in Ronald P. Evens, Biotechnology, 2020
Transgenic animals are a special genetics-related development in biotechnology, as well as all drug development that enhances the screening of potential therapeutic molecules. Through genetic engineering, an animal’s genetic makeup (often in mice and rats) is altered by knocking out the animal’s normal genes and inputting a human gene that can produce a target disease, which results in the animal presenting with a disease that is more human-like in its pathology, essentially a human disease model in a rat. A potential new drug candidate is administered to these transgenic animals, and the animal’s disease model will better predict (respond to) the drug’s action as being representative of what would really occur in humans.
Nucleic Acids
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
Transgenic animals are laboratory animals which have overexpressed certain genes or can carry genes for various human diseases. Alternatively, they can lack some genes or have a target gene inactivated. These are the so-called knock-out animals and are useful models for the studies of atherosclerosis, hypercholesterolemia, osteoporosis, spontaneous tumors (lack of p53 protein), cystic fibrosis, thalassemia, Duchenne muscular dystrophy, sickle cell anemia, and other diseases. Severe combined immunodeficient (SCID) mice can grow various human tumor xenographs and are used in investigations of human cancers.
The state of the art of fetal hemoglobin-inducing agents
Published in Expert Opinion on Drug Discovery, 2022
Aline Renata Pavan, Juliana Romano Lopes, Jean Leandro Dos Santos
Few of the prototypes determined from the phenotypic assays were analyzed in vivo using transgenic animals or even used in clinical trials. The prototypes that underwent clinical trials had short-chain fatty acids [23]. The effect of short-chain fatty acids on HbF-inducers was reported for butyrates, and clinical trials evaluating sodium 2,2-dimethylbutyrate showed a slight increase in HbF of 0.2 g/dL (NCT01322269) [24]. The low efficacy of short-chain fatty acids could be attributed to irregular pharmacokinetics. Despite these concerns, such compounds are identified through HTS as HbF-inducing agents. Using the double-luciferase reporter assay, three promising short-chain fatty acids were evaluated in vivo in non-anemic transgenic mice and anemic baboons. βYAC transgenic mice treated with those compounds (500 mg/Kg) showed a two-fold increase (approximately) in the γ-globin mRNA levels relative to the baseline levels. In juvenile baboons, these compounds increased the levels of F-reticulocytes 2-fold to 15-fold and the total hemoglobin levels by 1 to 2 g/dL per week relative to the baseline levels [23].
A de novo c.113 T > C: p.L38R mutation of SPTLC1: case report of a girl with sporadic juvenile amyotrophic lateral sclerosis
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Xiaoxuan Liu, Ji He, Weiyi Yu, Dongsheng Fan
But why does a mutation of a ubiquitously expressed gene result in selective loss of motor neurons? Most of the variants of SPTLC1-associated JALS are located at the exon2 (Figure 1(E)), including a variant p. Leu39del, which is very close to our variant (p. Leu38Arg). Recent studies have identified a negative regulation of sphingolipid biosynthesis for exon 2 of SPTLC1 in the homeostatic regulation of SPT mediated by binding ORMDL3 (4). SPT/ORMDL3 complex abnormality may lead to increase de-novo ceramide synthesis and subsequently increased ceramide and sphingolipids. Ceramide is a bioactive intracellular signal molecular that mediates neuronal differentiation, apoptosis, autophagy and inflammation, which are all underlying pathological mechanisms of ALS. Excess ceramide could induce mitochondrial dysfunction and impair respiratory capacity by the increase of oxidative stress, depletion of ATP and apoptosis (13–15). Inhibition of sphingolipid synthesis prevents the accumulation of ceramides and sphingomyelin and protects motor neurons against death induced by oxidative and excitotoxic insults (14). Further studies in both cell culture and transgenic animals will be required. The p. Leu38Arg variant in our patient might impact negative regulation of SPT activity, which indicates that serine supplementation may worsen the phenotype and should be avoided.
How necessary are animal models for modern drug discovery?
Published in Expert Opinion on Drug Discovery, 2021
Transgenic animals have a foreign gene introduced into their genome. Such animals are usually produced by DNA microinjection into the pronuclei of a fertilized egg that is subsequently implanted into the oviduct of the surrogate mother. Transgenic animals have become a key tool in functional genomics in order to generate models for human diseases and validate new drugs [20]. Transgenesis includes the addition of foreign genetic information to animals and specific inhibition of endogenous gene expression. The knockout animals are transgenic that have a specific interest gene disabled are transgenic, and are widely used to investigate both normal gene function, as well as the analyses of patho-biological roles of select genes involved in various disease states [21]. In addition, such transgene/knockout animal models are actively used in the development of new therapeutics and associated strategies.