About

Gregory R. Grant, Ph.D., is a Research Associate Professor of Genetics at the University of Pennsylvania's Perelman School of Medicine. He serves as the Director of Bioinformatics at the Institute for Translational Medicine and Therapeutics (ITMAT). His research expertise focuses on high throughput sequencing analysis, with a main emphasis on RNA-Sequencing. He is an expert in a wide range of statistical methods in biology, including study design and non-parametric methods, and has extensive programming experience. His work encompasses transcriptomics, functional genomics, cancer genomics, microarray analysis, and array CGH. Dr. Grant's contributions include developing and applying bioinformatics tools and methods to analyze complex biological data, advancing understanding in areas such as circadian rhythms, age-related molecular changes, and disease mechanisms.

Research topics

• Biology
• Computational biology
• Medicine
• Genetics
• Computer science

Selected publications

• Age and the Diurnal Oscillatory Features of the Human Chronobiome

  medRxiv · 2026-01-23 · 2 citations

  article

  The molecular clock regulates diverse aspects of human biology. As people age, diurnal rhythms deteriorate, most evidently in the daytime napping and nighttime waking of older individuals. To understand how temporal deconsolidation of oscillatory networks could contribute to age-related disease expression, we studied the chronobiome at unprecedented depth in young and old apparently healthy individuals. Transomic integration segregated age groups and identified candidate mechanisms by which oscillatory function might contribute to age dependent distinctions. In an orthogonal approach, we validated as true cyclers many proteins identified in the UK Biobank as predictors of health and disease outcomes. Here, age-specific alterations in the cycling proteome across disease phenotypes is consistent with our hypothesis that deconsolidated circadian programs associate with increased susceptibility to age-related disease.

  PublisherDOI

• The before, during, and after of emergency swine depopulation with foam

  AASV Annual Meeting · 2025-02-15

  article1st authorCorresponding
  PublisherDOI

• Sources of non-uniform coverage in short-read RNA-Seq data

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-31 · 2 citations

  preprintOpen accessSenior author

  The origin of several normal cellular functions and related abnormalities can be traced back to RNA splicing. As such, RNA splicing is currently the focus of a vast array of studies. To quantify the transcriptome, short-read RNA-Seq remains the standard assay. The primary technical artifact of RNASeq library prep, which severely interferes with analysis, is extreme non-uniformity in coverage across transcripts. This non-uniformity is present in both bulk and single-cell RNA-Seq and is observed even when the sample contains only full-length transcripts. This issue dramatically affects the accuracy of isoform-level quantification of multi-isoform genes. Understanding the sources of this non-uniformity is critical to developing improved protocols and analysis methods. Here, we explore eight potential sources of non-uniformity. We demonstrate that it cannot be explained by one factor alone. We performed targeted experiments to investigate the effect of fragment length, PCR ramp rate, and ribosomal depletion. We assessed existing data sets with varying sample quality, PCR cycle number, reverse transcriptase, and technical or biological replicates. We found evidence that interference of reverse transcription by secondary structure is unlikely to be the major contributing factor, that rRNA pull-down methods do not cause non-uniformity, that PCR ramp rate does not substantially impact non-uniformity, and that shorter fragments do not reduce non-uniformity. All these findings contradict prior publications or recommendations.

  PublisherOA PDFDOI

• Ethnic Disparities in Cytomegalovirus Infection Among Zero-A-B-DR Mismatched Kidney Transplant Recipients

  American Journal of Transplantation · 2025-08-01

  article
  PublisherDOI

• Effect of external cues on clock-driven protection from Influenza A infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-11

  preprintOpen access

  Abstract Influenza and other respiratory viral pathogens are leading causes of mortality and morbidity. We previously demonstrated that circadian rhythms confer temporal protection from influenza infection. Here, we investigated whether this protection requires rhythmic function after the initial infection by manipulating environmental cycles. We demonstrate that disrupting environmental lighting cues within a critical window of vulnerability abrogates time-of-day specific protection. This poor outcome is mediated by a dysregulated immune response, evidenced by the accumulation of inflammatory monocytes and CD8 + cells in the lungs and a transcriptomic profile indicative of an exaggerated immune response. Disruption of the light cycle does not affect outcomes in a clock mutant, indicating that it acts by compromising endogenous timekeeping. Importantly, rhythmic meal timing mitigates the adverse effects of disrupted light cycles, suggesting that external cycling cues, which act through different body clocks, can substitute for each other. Our findings highlight the crucial interplay between environmental factors and endogenous clocks in shaping influenza outcomes, offering significant translational potential for improving the care of critically ill patients with respiratory viral infections.

  PublisherOA PDFDOI

• Effect of external cues on clock-driven protection from influenza A infection

  Journal of Clinical Investigation · 2025-11-16

  articleOpen access

  Influenza and other respiratory viral pathogens remain leading causes of mortality and morbidity. Circadian rhythms play a critical role in regulating immune responses and can confer temporal protection from influenza infection. Here, we investigated whether this protection requires rhythmic function after the initial infection by manipulating environmental cycles. We found that disrupting environmental lighting cues within a critical window of vulnerability abrogated the time-of-day-specific protection. This poor outcome was mediated by a dysregulated immune response, as evidenced by the accumulation of inflammatory monocytes and CD8+ T cells in the lungs and a transcriptomic profile indicative of an exaggerated inflammation. Disruption of the light cycle did not affect outcomes in a clock mutant, indicating that it acts through the host's circadian clock. Importantly, rhythmic meal timing mitigated the adverse effects of disrupted light cycles, supporting the idea that external cues acting through different body clocks can compensate for one another. Together, these findings underscore the critical interplay between environmental timing cues and endogenous circadian rhythms in determining influenza outcomes and offer translational insight into optimizing care for critically ill patients with respiratory viral infections.

  PublisherDOI

• Generating correlated data for omics simulation

  PLoS Computational Biology · 2025-09-05

  articleOpen accessCorresponding

  Simulation of realistic omics data is a key input for benchmarking studies that help users obtain optimal computational pipelines. Omics data involves large numbers of measured features on each sample and these measures are generally correlated with each other. However, simulation too often ignores these correlations, perhaps due to computational and statistical hurdles of doing so. To alleviate this, we describe three approaches for generating omics-scale data with correlated measures which mimic real datasets. These approaches are all based on a Gaussian copula approach with a covariance matrix that decomposes into a diagonal part and a low-rank part. This decomposition allows for extremely efficient simulation, overcoming a hurdle for adoption of past methods. We use these approaches to demonstrate the importance of including correlation in two benchmarking applications. First, we show that variance of results from the popular DESeq2 method increases when dependence is included. Second, we demonstrate that CYCLOPS, a method for inferring circadian time of collection from transcriptomics, improves in performance when given gene-gene dependencies in some circumstances. We provide an R package, dependentsimr, that has efficient implementations of these methods and can generate dependent data with arbitrary marginal distributions, including discrete (binary, ordered categorical, Poisson, negative binomial), continuous (normal), or with an empirical distribution.

  PublisherOA PDFDOI

• Role of IL10 signaling in the circadian control of host response to Influenza infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-10

  preprintOpen access

  Abstract We have previously demonstrated that the circadian clock regulates the host response to influenza A virus (IAV) infection, conferring a time-of-day-specific protection –infection at dawn resulted in a threefold increase in survival and reduced immunopathology compared to infection at dusk. While IL10 is well-known for its immunoregulatory function, its role in IAV remains unclear, with studies reporting both protective and detrimental effects. Given the diurnal rhythmicity of IL-10 receptor ( Il10ra ) expression in the lung, we investigated the contribution of IL-10 signaling to time-of-day-specific IAV protection. We found that blocking IL10 signaling abrogated the time of day protection, leading to increased immunopathology characterized by enhanced lymphocyte infiltration and global immune activation (transcriptomic analysis). Interestingly, while later, IL-10R blockade also eliminated the time-of-day difference in IAV outcomes, it improved the outcome of dusk-infected mice. Furthermore, natural killer (NK) cell depletion suppressed IL-10 levels in bronchoalveolar lavage, suggesting a role for NK cells in regulating IL-10 signaling. In conclusion, incorporating the circadian context has not only clarified the IL-10 role in IAV infection but also underscored the pivotal influence of circadian regulation on immune responses.

  PublisherOA PDFDOI

• Degree of Cyclooxygenase-2 Inhibition Modulates Blood Pressure Response

  Hypertension · 2025-12-29 · 1 citations

  articleOpen access

  BACKGROUND: Large clinical trials compared distinct nonsteroidal anti-inflammatory drugs in terms of their risk of adverse cardiovascular events. However, whether pharmacologically equipotent doses were used, that is, whether a similar degree of COX (cyclooxygenase)-2 inhibition was achieved, was not considered. We compared drug target inhibition and blood pressure (BP) response to celecoxib and naproxen. METHODS: Sixteen healthy participants were treated with celecoxib (200 mg/d), naproxen (500 mg/d), or placebo for 7 days in a double-blind, crossover design. The degree of COX inhibition was assessed ex vivo using established whole blood assays and in vivo by quantifying urinary metabolites of thromboxane A 2 (COX-1) and prostacyclin (COX-2). Ambulatory BP was measured throughout the final dosing interval. RESULTS: Both nonsteroidal anti-inflammatory drugs inhibited COX-2 activity relative to placebo, but naproxen inhibited COX-2 activity to a greater degree (62.9±21.7%) than celecoxib (35.7±25.2%; P <0.05). Similarly, naproxen treatment inhibited prostacyclin formation in vivo (48.0±24.9%) to a greater degree than celecoxib (26.7±24.6%; P <0.05). Naproxen significantly increased BP compared with celecoxib (mean arterial pressure, +2.5 [95% CI, 1.5–3.5] mm Hg; systolic BP, +4.0 [95% CI, 2.9–5.1] mm Hg; and diastolic BP, +1.8 [95% CI, 0.8–2.8] mm Hg; P <0.05 for all). The difference in systolic BP relative to placebo was associated with the degree of COX-2 inhibition ( P <0.05). CONCLUSIONS: Future studies should consider pharmacokinetic and pharmacodynamic properties, as well as patient-specific factors that may modulate the cardiovascular risk of nonsteroidal anti-inflammatory drug use. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02502006.

  PublisherOA PDFDOI

• Circadian Control of Pulmonary Endothelial Signaling Occurs via the NADPH Oxidase 2-NLRP3 Pathway

  Journal of Biological Rhythms · 2025-09-14

  articleOpen access

  Circadian rhythms are endogenous oscillations that occur with a 24-h periodicity and support organismal homeostasis. While the role of the circadian clock in systemic vasculature is well known, its role in pulmonary vasculature, specifically in the pulmonary endothelium, has remained unexplored. We hypothesized that the circadian clock directly regulates pulmonary endothelium to control lung inflammation. Using pulmonary artery segments and endothelial cells isolated from lungs of mPer2luciferase transgenic mice, we monitored circadian rhythms and observed that lipopolysaccharide (LPS) treatment disrupted rhythmicity. This disruption was mediated by reactive oxygen species (ROS) generated via NADPH oxidase 2 (NOX2). Remarkably, the pharmacologic inhibition of NOX2 before LPS exposure restored circadian rhythmicity in the pulmonary endothelium. In wild-type (WT) mice, LPS activated a NOX2-NLRP3 signaling axis that drove inflammation as evidenced by increased polymorphonuclear neutrophil (PMN) accumulation and intercellular adhesion molecule-1 (ICAM-1) expression on the pulmonary endothelium. In contrast, disruption of the clock using two different clock mutants ( Bmal 1 –/– and Cry1/2 –/– ) resulted in a sustained baseline elevation of PMN and ICAM-1, which changed minimally with LPS. This effect was attributed to aberrant activation of the NLRP3 inflammasome at baseline in the clock mutants, as supported by lung transcriptomic data and reversal of the phenotype with an NLRP3 inhibitor. Importantly, these findings also reveal an intriguing bidirectional relationship: while the circadian clock modulates inflammatory responses, inflammatory stimuli in turn alter circadian rhythmicity via the NOX2 pathway. Together, our results identify a novel mechanism by which circadian control of pulmonary endothelial inflammation may be leveraged to mitigate the consequences of clock disruption in lung disease.

  PublisherDOI

Recent grants

• NIH Grant K25HG000052

  NIH · $571k · 2005

Frequent coauthors

• Nicholas F. Lahens

  Translational Therapeutics (United States)

  150 shared

• Garret A. FitzGerald

  Translational Therapeutics (United States)

  121 shared

• Christian J. Stoeckert

  University of Pennsylvania

  97 shared

• Thomas G. Brooks

  75 shared

• Dimitra Sarantopoulou

  National Institutes of Health

  68 shared

• Antonijo Mrčela

  Translational Therapeutics (United States)

  67 shared

• Tilo Großer

  Bielefeld University

  62 shared

• Carsten Skarke

  University of Pennsylvania

  60 shared

Labs

• ITMAT Bioinformatics LaboratoryPI

Education

• masters, computer science

  University of Pennsylvania

  1999

• PhD, mathematics

  University of Maryland University College

  1995

• Bachellors, mathematics

  University of Maryland University College

  1988