About

Michael M. Grunstein, M.D., Ph.D., is an Emeritus Professor of Pediatrics (Pulmonary Medicine) at the University of Pennsylvania's Perelman School of Medicine. His research focuses on identifying genes and molecular signaling pathways that underlie the altered airway function characteristic of asthma. His laboratory has demonstrated that airway smooth muscle (ASM) exhibits a synthetic phenotype of inflammatory cytokine production when sensitized by specific pro-asthmatic risk factors, including IgE immune complexes, respiratory pathogens, and dust mite allergens. He has shown that sensitized ASM and T lymphocytes cooperate through intercellular signaling to elicit cytokine release, which contributes to pro-asthmatic changes in airway responsiveness. His work has elucidated the role of MAPK signaling pathways, particularly ERK1/2 and p38, in mediating these effects, and has identified mechanisms involving ASM presentation of superantigens to T cells and cross-talk between protein kinase A and ERK1/2 pathways. These findings have provided a foundation for developing new pharmacological treatments targeting specific receptor-coupled molecular pathways in airway smooth muscle. Additionally, Dr. Grunstein's research includes gene expression profiling and genome-wide association studies aimed at uncovering genetic variants associated with pediatric asthma phenotypes, with the goal of advancing targeted therapies for asthma.

Research topics

• Biology
• Medicine
• Internal medicine
• Endocrinology
• Cell biology

Selected publications

• Exploring the Potential of Psychedelics in the Treatment of Headache Disorders: Clinical Considerations and Exploratory Insights

  Current Pain and Headache Reports · 2025-01-16 · 4 citations

  review
  PublisherDOI

• Multimodal Approach to NMOSD Relapse Treatment: Experience with Two Cases (P10-8.011)

  Neurology · 2025-04-07

  article1st authorCorresponding

  To describe two patients with seropositive neuromyelitis optica spectrum disorder (NMOSD) who were treated with solumedrol, plasma exchange (PLEX), and eculizumab.

  PublisherDOI

• A Tale of Two Cases: When to Use PLEX That is The Question (P10-5.025)

  Neurology · 2023-04-25 · 1 citations

  article

  NA

  PublisherDOI

• Homeostatic glucocorticoid signaling in airway smooth muscle: A roadmap to asthma pathogenesis

  Frontiers in Endocrinology · 2023-01-04 · 1 citations

  articleOpen access1st authorCorresponding

  Homeostasis is the self-regulating process by which the body maintains internal stability within a narrow physiological range (i.e., "normality") as it dynamically adjusts to disruptive influences. Thus, whereas homeostasis maintains bodily health, disrupted homeostasis at the tissue or systemic level leads to disease. Airway smooth muscle (ASM) is the pivotal site of disrupted homeostasis in asthma. While extensive research has greatly expanded our understanding of ASM behavior under pro-asthmatic conditions, the cellular signaling mechanisms that underlie ASM homeostasis under these conditions remain elusive. Based on a broad collection of published studies, a homeostasis mechanism intrinsic to ASM and exhibited under inflammatory and non-inflammatory pro-asthmatic conditions is identified herein. Central to this mechanism is the novel unifying concept that the pro-asthmatic-exposed ASM can independently generate its own active glucocorticoid (i.e., cortisol), produce its own newly activated glucocorticoid receptors for the steroid, and, accordingly, use this molecular strategy to homeostatically prevent induction of the asthmatic state. This article addresses the experimental evidence that underlies the proposed homeostatic glucocorticoid signaling mechanism in ASM, followed by a discussion and depiction of the feed-forward and feedback intrinsic ASM signaling circuitry that constitutes the homeostatic state. The proposed mechanism offers a practical roadmap for future basic and translational research aimed at identifying potential key site(s) of disrupted ASM homeostasis leading to asthma.

  PublisherOA PDFDOI

• Cotranscriptional Set2 Methylation of Histone H3 Lysine 36 Recruits a Repressive Rpd3 Complex

  UNC Libraries · 2021-06-24

  articleOpen access

  SummaryThe yeast histone deacetylase Rpd3 can be recruited to promoters to repress transcription initiation. Biochemical, genetic, and gene-expression analyses show that Rpd3 exists in two distinct complexes. The smaller complex, Rpd3C(S), shares Sin3 and Ume1 with Rpd3C(L) but contains the unique subunits Rco1 and Eaf3. Rpd3C(S) mutants exhibit phenotypes remarkably similar to those of Set2, a histone methyltransferase associated with elongating RNA polymerase II. Chromatin immunoprecipitation and biochemical experiments indicate that the chromodomain of Eaf3 recruits Rpd3C(S) to nucleosomes methylated by Set2 on histone H3 lysine 36, leading to deacetylation of transcribed regions. This pathway apparently acts to negatively regulate transcription because deleting the genes for Set2 or Rpd3C(S) bypasses the requirement for the positive elongation factor Bur1/Bur2.

  PublisherDOI

• Dissecting Nucleosome Free Regions by a Segmental Semi-Markov Model

  UNC Libraries · 2020-11-07

  articleOpen access

  BackgroundNucleosome free regions (NFRs) play important roles in diverse biological processes including gene regulation. A genome-wide quantitative portrait of each individual NFR, with their starting and ending positions, lengths, and degrees of nucleosome depletion is critical for revealing the heterogeneity of gene regulation and chromatin organization. By averaging nucleosome occupancy levels, previous studies have identified the presence of NFRs in the promoter regions across many genes. However, evaluation of the quantitative characteristics of individual NFRs requires an NFR calling method.MethodologyIn this study, we propose a statistical method to identify the patterns of NFRs from a genome-wide measurement of nucleosome occupancy. This method is based on an appropriately designed segmental semi-Markov model, which can capture each NFR pattern and output its quantitative characterizations. Our results show that the majority of the NFRs are located in intergenic regions or promoters with a length of about 400–600bp and varying degrees of nucleosome depletion. Our quantitative NFR mapping allows for an investigation of the relative impacts of transcription machinery and DNA sequence in evicting histones from NFRs. We show that while both factors have significant overall effects, their specific contributions vary across different subtypes of NFRs.ConclusionThe emphasis of our approach on the variation rather than the consensus of nucleosome free regions sets the tone for enabling the exploration of many subtler dynamic aspects of chromatin biology.

  PublisherDOI

• What It’s Like to be a Future Neurologist: A Medical Student’s Perspective

  Acta Scientific Neurology · 2020-03-20

  articleOpen access1st authorCorresponding
  PublisherDOI

• Genetics, Biochemistry, and “Simple” Organisms Converge to Unlock Secrets in Histone Biology

  JAMA · 2018-09-12 · 4 citations

  article1st authorCorresponding

  Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal

  PublisherDOI

• responsiveness of IgE-sensitized airway smooth muscle IL-13-dependent autocrine signaling mediates altered

  2016-01-01

  article1st authorCorresponding
  Publisher

• Constitutively Active Signaling by the G Protein βγ-Subunit Mediates Intrinsically Increased Phosphodiesterase-4 Activity in Human Asthmatic Airway Smooth Muscle Cells

  PLoS ONE · 2015-03-05 · 6 citations

  articleOpen accessSenior authorCorresponding

  Signaling by the Gβγ subunit of Gi protein, leading to downstream c-Src-induced activation of the Ras/c-Raf1/MEK-ERK1/2 signaling pathway and its upregulation of phosphodiesterase-4 (PDE4) activity, was recently shown to mediate the heightened contractility in proasthmatic sensitized isolated airway smooth muscle (ASM), as well as allergen-induced airway hyperresponsiveness and inflammation in an in vivo animal model of allergic asthma. This study investigated whether cultured human ASM (HASM) cells derived from asthmatic donor lungs exhibit constitutively increased PDE activity that is attributed to intrinsically upregulated Gβγ signaling coupled to c-Src activation of the Ras/MEK/ERK1/2 cascade. We show that, relative to normal cells, asthmatic HASM cells constitutively exhibit markedly increased intrinsic PDE4 activity coupled to heightened Gβγ-regulated phosphorylation of c-Src and ERK1/2, and direct co-localization of the latter with the PDE4D isoform. These signaling events and their induction of heightened PDE activity are acutely suppressed by treating asthmatic HASM cells with a Gβγ inhibitor. Importantly, along with increased Gβγ activation, asthmatic HASM cells also exhibit constitutively increased direct binding of the small Rap1 GTPase-activating protein, Rap1GAP, to the α-subunit of Gi protein, which serves to cooperatively facilitate Ras activation and, thereby, enable enhanced Gβγ-regulated ERK1/2-stimulated PDE activity. Collectively, these data are the first to identify that intrinsically increased signaling via the Gβγ subunit, facilitated by Rap1GAP recruitment to the α-subunit, mediates the constitutively increased PDE4 activity detected in asthmatic HASM cells. These new findings support the notion that interventions targeted at suppressing Gβγ signaling may lead to novel approaches to treat asthma.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HL031467

  NIH · $4.7M · 2009

• NIH Grant R01GM031336

  NIH · $93k · 1987

• NIH Grant R01HL058245

  NIH · $1.5M · 2003

• NIH Grant R01HL097739

  NIH · $1.6M · 2013

• NIH Grant R01GM023674

  NIH · $6.3M · 2013

Frequent coauthors

• Håkon Håkonarson

  University of Pennsylvania

  136 shared

• Judith S. Grunstein

  80 shared

• Sing Chuang

  University of Pennsylvania

  75 shared

• Neil Maskeri

  University of Pennsylvania

  62 shared

• Craig M. Schramm

  Connecticut Children's Medical Center

  47 shared

• Aihua Hu

  42 shared

• D Herrick

  36 shared

• Gustavo Niño

  Children's National

  36 shared