The nuclear receptor superfamily is a group of intracellular transcription factors that directly regulate gene expression in response to lipophilic molecules. These receptors are found in metazoan organisms such as nematodes, insects, and vertebrates. Nuclear receptors affect a wide variety of physiologic functions including development, reproduction, and metabolism and are associated with diseases such as Alzheimer’s, cancer, and diabetes.
An animal model is a non-human species that has been widely studied and used during research to help understand biological processes in a laboratory setting. The use of animal models as human surrogates has provided a great deal of information about physiology and disease with over 150 Nobel Prizes awarded in physiology or medicine to professionals utilizing animal models for their research.
The primary reason for the use of animal models is the evolutionary principle that all organisms share some degree of relatedness and genetic similarity. Vertebrate models in particular are useful as human surrogates in drug discovery and medical research due to their more common ancestry. Though there are many vertebrates that could be used, a few are more common in research than others.
Growth factors are proteins that stimulate the growth of specific tissues. They bind to cells by growth factor receptors, activating cellular proliferation and differentiation. This activation of growth factor receptors creates a short, time-limited signal, which causes different parts of cellular proliferation and differentiation such as mitosis, clonal expansion, gene regulation, and cell apoptosis. While growth factor receptors operate on different cell types, their signal pathways often overlap, which makes them important targets for oncology research.
First discovered by Rita Levi-Montalcini, growth factors are compact polypeptides, that bind to transmembrane receptors harboring kinase activity, to stimulate specific combinations of intracellular signaling pathways. The intracellular signaling pathways that are activated by growth factors are mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), phospholipase C-γ, and transcription factors like the signal transducers and activators of transcription (STATs) or SMAD proteins. This activation of growth factor receptors creates a short, time-limited signal, which causes different parts of cellular proliferation and differentiation such as mitosis, clonal expansion, gene regulation, and cell apoptosis. Unlike hormones which have a wider systemic influence, growth factors usually transmit signals between cells to modulate their activity. They act as chemical messengers, communicating with different cells to stimulate growth. Depending on their function, growth factors can produce endocrine, paracrine, autocrine, or juxtracrine responses in cells.
The assessment of a drug candidate’s cross-activity with human xenobiotic-sensing receptors provides important early indications of that drug’s potential for downstream drug-drug interactions or other toxicology concerns. Prior to moving into human trials, preclinical studies utilize animals as human surrogates to assess a drug’s pharmacokinetic and toxicologic profiles. A wide range of animal models are used in preclinical studies for drug discovery including mice, rats, dogs, zebrafish, rabbits, and non-human primates. In research, these animals are used because they are orthologs. Orthologs are animals of different species that share genes that evolved from a common ancestor and have retained a similar function to those genes in humans.
The zebrafish (Danio rerio) is a small fish that has been making big waves as a popular vertebrate model for research. Zebrafish are a species of tropical fresh-water fish, that are native to southeast Asia specifically India, Nepal, Bhutan, Pakistan, Bangladesh, and Myanmar. Zebrafish live in schools and range from about 1 inch to 1.5 inches long. The name “zebrafish” comes from the blue stripes on both sides of their bodies and because of this, zebrafish were found in pet stores around the U.S long before they were used for research.
The discovery process is time consuming and expensive, and it is becoming increasingly more important that if you do fail that you fail fast before moving onto clinical trials. When planning your research, there are different options to test compounds for nuclear receptor activation or hepatotoxicity. The project might include performing cell-based reporter assays and if it does, you may consider designing your own assay rather than working with a company who specializes in this work. Before adding the process of designing an assay to a new project, consider these three important questions.
Modern drug discovery involves the identification of screening hits, medicinal chemistry, and optimization of those hits to increase the affinity, selectivity, efficacy/potency, metabolic stability, and bioavailability. This process is time-consuming, costly, and risky. Nuclear receptors are ideal targets for drug discovery. They control a variety of biological and disease processes through the expression of specific genes. Nuclear receptors do this by binding to lipophilic substances known as ligands.
Pharmacotherapy is based on the interplay of pharmacokinetics and pharmacodynamics, which allows scientists to understand the effect drugs have on the human body and helps researchers develop drugs that are safe and effective. These two concepts explain how the body impacts drugs (pharmacokinetics) and how those drugs can then impact the body (pharmacodynamics).
Biliary excretion is the crucial process of removing drugs from the human body and it plays an important role in drug processing. Researchers and drug development teams frequently examine this active process relative to differences in drug responses and challenges with drug toxicity.
