How Surrogate and Chemical Genetics in Model Organisms Can Suggest Therapies for Human Genetic Diseases

Strynatka, Katherine A; Gurrola-Gal, Michelle C; Berman, Jason N.; McMaster, Christopher R.

doi:10.1534/genetics.117.300124

Cited by 18 publications

(26 citation statements)

References 238 publications

(239 reference statements)

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“…2). Around the same time, researchers started to use phenotypic screens and genomic manipulation to paint a picture of cellular replication and the normal state of the cell, mainly in yeast as a model organism (Fraczek, Naseeb, & Delneri, 2018;Strynatka, Gurrola-Gal, Berman, & McMaster, 2018). The combination of these approaches in the late 1980s resulted in the birth of chemical genetics and led to many powerful developments such as directed evolution of enzymes, phage display of peptides and antibodies, and further refinement of target-based HTS (e.g.…”

Section: Evolution Of Screening Technologies For Drug Discoverymentioning

confidence: 99%

“…The combination of these approaches in the late 1980s resulted in the birth of chemical genetics and led to many powerful developments such as directed evolution of enzymes, phage display of peptides and antibodies, and further refinement of target-based HTS (e.g. combinatorial chemistry, split-and-pool synthesis and fragment-based discovery) (Furka, Asgedom, & Diboa, 1988;Smith, 1985;Strynatka et al, 2018) (Fig. 2).…”

Section: Evolution Of Screening Technologies For Drug Discoverymentioning

confidence: 99%

“…2). From the late 1980s to the beginning of the 1990s, the use of animal models shifted to cell-based screens that minimized the number of reagents required and allowed the output of screens to increase (Strynatka et al, 2018) (Fig. 2).…”

Section: Evolution Of Screening Technologies For Drug Discoverymentioning

confidence: 99%

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Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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Section: Evolution Of Screening Technologies For Drug Discoverymentioning

confidence: 99%

Section: Evolution Of Screening Technologies For Drug Discoverymentioning

confidence: 99%

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Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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“…Saccharomyces cerevisiae is a powerful model system for understanding the 52 complex processes that direct cellular function and underpin many human diseases 53 (Birkeland et al 2010; Botstein and Fink 2011; Kachroo et al 2015;Hamza et al 2015, 54 2020; Wangler et al 2017;Strynatka et al 2018). Mutant hunts (i.e.…”

Section: Introduction 51mentioning

confidence: 99%

MutantHuntWGS: A Pipeline for IdentifyingSaccharomyces cerevisiaeMutations

Ellison

Walker

Ropp

et al. 2020

Preprint

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37MutantHuntWGS is a user-friendly pipeline for analyzing Saccharomyces cerevisiae 38 whole-genome sequencing data. It uses available open-source programs to: (1) perform 39 sequence alignments for paired and single-end reads, (2) call variants, and (3) predict 40 variant effect and severity. MutantHuntWGS outputs a shortlist of variants while also 41 enabling access to all intermediate files. To demonstrate its utility, we use 42 MutantHuntWGS to assess multiple published datasets; in all cases, it detects the same 43 causal variants reported in the literature. To encourage broad adoption and promote 44 reproducibility, we distribute a containerized version of the MutantHuntWGS pipeline 45 that allows users to install and analyze data with only two commands. The 46 MutantHuntWGS software and documentation can be downloaded free of charge from 47 https://github.com/mae92/MutantHuntWGS. 48 49 50

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“…Genetic diseases can be both inherited and acquired. In particular, most of the inherited diseases belong to the category called “orphan diseases” ( Strynatka et al, 2018 ). The term orphan disease can refer to two different types: common diseases neglected by doctors or rare diseases with a variable incidence in the population ( Aronson, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

Rare Genetic Blood Disease Modeling in Zebrafish

Rissone

Burgess

2018

Front. Genet.

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Hematopoiesis results in the correct formation of all the different blood cell types. In mammals, it starts from specific hematopoietic stem and precursor cells residing in the bone marrow. Mature blood cells are responsible for supplying oxygen to every cell of the organism and for the protection against pathogens. Therefore, inherited or de novo genetic mutations affecting blood cell formation or the regulation of their activity are responsible for numerous diseases including anemia, immunodeficiency, autoimmunity, hyper- or hypo-inflammation, and cancer. By definition, an animal disease model is an analogous version of a specific clinical condition developed by researchers to gain information about its pathophysiology. Among all the model species used in comparative medicine, mice continue to be the most common and accepted model for biomedical research. However, because of the complexity of human diseases and the intrinsic differences between humans and other species, the use of several models (possibly in distinct species) can often be more helpful and informative than the use of a single model. In recent decades, the zebrafish (Danio rerio) has become increasingly popular among researchers, because it represents an inexpensive alternative compared to mammalian models, such as mice. Numerous advantages make it an excellent animal model to be used in genetic studies and in particular in modeling human blood diseases. Comparing zebrafish hematopoiesis to mammals, it is highly conserved with few, significant differences. In addition, the zebrafish model has a high-quality, complete genomic sequence available that shows a high level of evolutionary conservation with the human genome, empowering genetic and genomic approaches. Moreover, the external fertilization, the high fecundity and the transparency of their embryos facilitate rapid, in vivo analysis of phenotypes. In addition, the ability to manipulate its genome using the last genome editing technologies, provides powerful tools for developing new disease models and understanding the pathophysiology of human disorders. This review provides an overview of the different approaches and techniques that can be used to model genetic diseases in zebrafish, discussing how this animal model has contributed to the understanding of genetic diseases, with a specific focus on the blood disorders.

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How Surrogate and Chemical Genetics in Model Organisms Can Suggest Therapies for Human Genetic Diseases

Cited by 18 publications

References 238 publications

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

MutantHuntWGS: A Pipeline for IdentifyingSaccharomyces cerevisiaeMutations

Rare Genetic Blood Disease Modeling in Zebrafish

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