Nath Research Lab

1. Illuminating the Function of the Human Druggable Genome—Big Data Meets Little Fish

There is a sea of human genomic data that has been published. Although these genetic findings have been associated with diseases or clinical traits, very few have demonstrated that these genetic changes play a causative role in disease process or can even postulate how these genetic changes play a role in disease development. To bridge this gap, we will layer biochemical datasets from human cohorts on top of these genetic findings, thereby generating a molecular clue as to how these genetic changes affect disease development. Our lab leverages these connections to direct further experimentation in zebrafish—an organism amenable to in vivo whole organism high-throughput assays with genetically encoded biosensors. Our efforts are currently focused on 134 druggable genes without known function. By framing these 134 genes into biochemical pathways, we hope to understand the mechanisms by which they contribute to human physiology and then develop drugs to target these genes.

2. Discovery and Development of Medical Countermeasures for Chemical Threats

Partnering with the NIH Countermeasures Against Chemical Threats Network, we formed a multi-institutional research consortium to discover and develop novel cyanide countermeasures. This work combines innovative high-throughput screening zebrafish with state-of-the-art metabolomics and three preclinical mammalian models. We are currently optimizing two lead compounds to meet BARDA requirements for advanced development and clinical deployment. This work addresses a critical unmet need for a medical countermeasure for deployment in mass casualty scenarios (NIH and Department of Homeland Security Directives). In addition to drug development, our drug discovery pipeline aims to elucidate the key metabolic derangements secondary to cyanide toxicity, highlighting new opportunities to intervene in cyanide toxicity. These novel compound classes and countermeasure mechanisms represent an opportunity to transform the field of cyanide countermeasures, which has not seen a new compound class emerge for several decades.

3. Gpr27—A Vastly Understudied G Protein-Coupled Receptor in the “Dark” Genome

Pharmacological modulation of GPCRs has proven to be one of the most successful stories in modern medicine; ~34% of all the FDA‐approved drugs target human GPCRs. Despite the widely recognized importance of this class of proteins in human biology, dozens of GPCRs remain understudied. For example, Gpr27 exhibits exceptionally high conservation among vertebrates, but its functions are virtually unknown. To elucidate the potential roles of Gpr27, we generated gpr27 knockout zebrafish and subjected them to a battery of assays in our metabolic phenotyping pipeline. We discovered a completely novel role for Gpr27 at the nexus of acylcarnitine metabolism and insulin resistance. These findings provide a new opportunity to intervene in metabolic syndromes in humans based on modulating Gpr27 signaling. Our current efforts are focused on discovering chemical scaffolds for the development of potent, selective compounds to modulate Gpr27 activity, in addition to elucidating the molecular underpinnings Gpr27 by leveraging our zebrafish model.

1. Nath AK, Ryu JH, Jin YN, Roberts LD, Dejam A, Gerszten RE, Peterson, RT. PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase Phosphorylation. Cell Reports. 2015; 10(5):  694-701. PMID: 25660020
• Research Highlights. Miura G. Go Fish. Nature Chemical Biology. 2015; 11: 304.
2. Nath AK, Shi X, Harrison DL, Morningstar JE, Mahon S, Chen A, Sips P, Lee J, Calum MA, Boss G, Brenner M, Gerszten RE, Peterson RT. Cisplatin confers protection against cyanide poisoning. Cell Chemical Biology. 2017; 24(5): 565-575. PubMed PMID: 28416275
3. Kimberly WT, O’Sullivan J, Nath AK, Keyes M, Yang Q, Larson MG, Ramachandran V, Peterson RT, Wang TJ, Corey K, Gerszten RE. Metabolite Profiling of Human Plasma Identifies Anandamide as a Biomarker of Nonalcoholic Steatohepatitis. JCI Insight. 2017; 2(9). PubMed PMID: 28469090
4. Sips P, Shi X, Musso G, Nath AK, Zhao Y, Nielson J, Morningstar J, Kelly AE, Mikell B, Buys E, Bebarta V, Rutter J, Davisson VJ, Mahon S, Brenner M, Boss G, Peterson RT, Gerszten RE, MacRae CA. Identification of specific metabolic pathways as druggable targets regulating the sensitivity to cyanide poisoning. PLoS One. 2018; 13(6):e0193889. PubMed PMID: 29879736
5. Morningstar J, Lee J, Hendry-Hofer T, Witeof A, Lyle LT, Knipp G, MacRae CA, Boss GR, Peterson RT, Davisson VJ, Gerszten RE, Bebarta VS, Mahon S, Brenner M, Nath AK. Intramuscular administration of hexachloroplatinate reverses cyanide-induced metabolic derangements and counteracts severe cyanide poisoning. FASEB BioAdvances. 2019; 1(2):81-92. https://doi.org/10.1096/fba.1024 PubMed PMID: 31355359
6. Nath AK, Ma J, Chen ZZ, Zhuyun L, Vitery MDC, Kelley ML, Peterson RT, Gerszten RE, Yeh JRJ. Genetic deletion of gpr27 alters acylcarnitine metabolism, insulin sensitivity, and glucose homeostasis in zebrafish. The FASEB Journal. 2020; 34:1546-1557. https://doi.org/10.1096/fj.20190 1466R PubMed PMID: 31914600
7. Ngo D, Benson MD, Long Z, Chen ZZ, Wang R, Nath AK, Keyes MJ, Shen DX, Sinha S, Kuhn E, Morningstar JE, Shi X, Peterson BD, Chan C, Katz D, Tahir U, Farrell LA, Melander O, Mosley JD, Carr SA, Ramachandran VS, Larson MG, Smith JG, Wang TJ, Yang Q, Gerszten RE. Proteomic Profiling Reveals Novel Biomarkers and Pathways in Type 2 Diabetes Risk. JCI Insight. 2021; 16:144392. https://doi.org/10.1172/jci.insight.144392 PubMed PMID: 33591955