Preprint Essay Version 1 Preserved in Portico This version is not peer-reviewed

Mechanistic Research for the Student or Educator (Part II of II)

Version 1 : Received: 19 September 2020 / Approved: 20 September 2020 / Online: 20 September 2020 (15:01:28 CEST)

How to cite: Leak, R. Mechanistic Research for the Student or Educator (Part II of II). Preprints 2020, 2020090482 (doi: 10.20944/preprints202009.0482.v1). Leak, R. Mechanistic Research for the Student or Educator (Part II of II). Preprints 2020, 2020090482 (doi: 10.20944/preprints202009.0482.v1).

Abstract

This two-part series describes how to test hypotheses on molecular mechanisms that underlie biological phenomena, using preclinical drug testing as a simplified example. While pursuing drug testing in preclinical research, it is important for students to understand the limitations of descriptive as well as mechanistic studies. The former does not identify any causal links between two or more variables; it identifies the presence or absence of correlations. The latter has caveats presented in Parts I and II of this series. Part II also describes how to test for a causal link between drug-induced activation of biological targets and therapeutic outcomes. Here, the mechanism of action of the drug is identified with pharmacological or genetic approaches that modify the expression/activity of the drug targets. Without interference with the proposed mechanism of action, a causal link between activation (or inhibition) of the target P and the therapeutic outcomes of drug D cannot be established. Using pharmacological agonists and antagonists, gene knockout and overexpression, or protein knockdown tools, designing a full-factorial three-way ANOVA forces the investigator to include the appropriate control groups, mitigating the risk of false positive or false negative conclusions. Upon completion of this series, the educator and student will have some of the tools in hand to design mechanistic studies and interpret various experimental outcomes, with knowledge of strengths and limitations of preclinical research.

Subject Areas

mechanistic; hypothesis; physiology; biology; pharmaceutical; biomedicine; preclinical

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