Laboratory for Pharmacological Innovation

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isom lab @ the university of miami

pH regulation of cell signaling systems

structural and chemical informatics

computational drug discovery

cell-based drug discovery

synthetic biology

cell stress

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RESEARCH PROGRAM

proton-gated coincidence detection

PH REGULATION OF G PROTEIN-COUPLED RECEPTORS (GPCRs)

G protein-coupled receptors (GPCRs) are both the largest class of cell surface receptors in humans, and the receptor family most targeted by therapeutic drugs. Major efforts in the lab are focused on understanding how coincident pH changes regulate GPCR drug and metabolite signaling. Our objective is to identify pH-intelligent GPCR inputs (in)capable of endomembrane signaling, and (in)sensitive to disease-related acidosis.

PH REGULATION OF CELL SURFACE RECEPTORS

Our lab studies proteins and cell-surface receptors that detect and transduce cellular signals. In certain biological scenarios—cancer, hypoxia, nutrient stress, inflammation, endocytosis—these signaling proteins encounter coincident acid signals. Our lab creates leading-edge experimental and computational approaches to illuminate how protons regulate these proteins and their constituent signaling and metabolic networks.

data science & drug/ligand discovery

PROTEIN ELECTROINFORMATICS

The need for pH regulation of molecular, cellular, and physiological processes is wide-ranging, as it exists in all domains of life and viruses. At the molecular level, pH changes act to regulate the structure, function, and interaction of proteins, RNA, DNA, lipids, metabolites, and drugs. pH effects in proteins, which are mediated by ionizable side chains and electrostatic forces, are difficult to predict from sequence and structure. In the lab we develop informatics algorithms to address this challenge.

STRUCTURAL AND CHEMICAL INFORMATICS

The discovery of new molecular therapeutics begins by searching for novel lead compounds. Building on the success of our algorithms for identifying pH sensitivities in proteins, we are developing new structure- and shape-based approaches for exploring new and unexpected areas of chemical space to predict new drug-like compounds. In the lab we test our predictions using cell-based (DCyFIRplex) and protein-based (fQCR) methods developed in our lab. Our unique ability to iteratively predict, validate, and refine our findings greatly expedites the discovery cycle.

protein design

CHIMERIC BIOSENSORS AND NANOBODIES

Using unbiased CRISPR engineering and rational structure-based design, we are creating biosensors, designer receptors, and targeted nanobody libraries. The major goals of this work are to 1) build tools for illuminating the molecular and cellular basis of proton sensing, 2) rationally design receptors for high-value chemical targets, and 3) efficiently and rationally mining nanobody-space for potential therapeutics and pharmacological tools.

3-D MAPPING OF INTRACELLULAR PH DYNAMICS AND PATTERNING

We are developing experimental and imaging analysis technologies that will illuminate the topological dynamics of cytoplasmic pH in response to external cues and a variety of physiologic stressors.

pH imaging

Our major computational work in the lab is focused on 1) mining protein structural information for actionable intelligence, 2) novel algorithms for structure-based drug design and vitrual screening, 3) software utilities that support our high-throughput CRISPR genome engineering pipeline, and 4) image analysis for 3D quantitation of organelle and intracellular pH dynamics. Most of our programs use computational geometry as a conceptual framework. We develop our own algorithms, primarily in Python, and use the incredible high performance computing infrastructure in place at the University of Miami to routinely undertake millions of calculations on thousands of protein structures.

We create leading-edge experimental techniques and platforms in yeast and human model systems that broadly support the testing and validation of our computational predictions. These include high-throughput CRISPR pipelines for creating large libraries of synthetic yeast strains (synBio), pooled cell-based experiments for massively multiplexed drug/ligand discovery, and chimeric prototyping of biosensors for cellular pH, cell signaling, and viral surveillance.

As such, the iterative compute-experiment-innovate cycle is wholly contained within the research group.

COMPUTATIONAL OVERVIEW

EXPERIMENTAL OVERVIEW

OUR APPROACH COMBINES COMPUTATION & EXPERIMENT

RESEARCH TEAM

DAN ISOM, PH.D.

PRINCIPAL INVESTIGATOR

DISOM at MIAMI.EDU

MCP GRADUATE STUDENT

JACOB ROWE

AFFILIATIONS

X

SENIOR RESEARCH ASSOCIATE

SANTIAGO VILAR, PH.D.

Dan began his undergraduate education pursuing a degree in fine art as a painting and sculpture major at the Cleveland Institute of Art, near where he was born and raised. After two years at CIA, Dan transitioned to a career in science, majoring in both Biochemistry and Chemistry at Case Western Reserve University, and earning his doctorate in Molecular Biophysics from Johns Hopkins University. Dan is currently a practicing molecular pharmacologist and biophysicist, systems and synthetic biologist, technologist, heavy CRISPR user, protein sequence- and structure-based informaticist, computational geometer, virtual screener, and python, medical, and graduate educator leading a talented and multidisciplinary research team at the University of Miami.