About

Kahlilia Morris-Blanco, PhD, is a Presidential Assistant Professor and core faculty member at the Penn Epigenetics Institute. She is also a faculty member at the Institute for Translational Medicine and Therapeutics, the Penn Cardiovascular Institute, and the Institute for Diabetes, Obesity and Metabolism within the University of Pennsylvania's Perelman School of Medicine. Her research investigates the role of epigenetics and mitochondrial dysfunction in aging and stroke pathophysiology, merging neuroscience, genomics, and biochemistry with neurological applications. Dr. Morris-Blanco's work focuses on understanding epigenetic mechanisms and mitochondrial pathways involved in neurological diseases, aiming to identify potential therapeutic targets for stroke and related conditions.

Research topics

• Medicine
• Neuroscience
• Biology
• Internal medicine
• Pharmacology

Selected publications

• TET3-Interacting LncRNA TILR Is Essential for DNA Hydroxymethylation–Mediated Neuroprotection After Ischemic Stroke

  Stroke · 2025-07-16 · 3 citations

  article

  BACKGROUND: Epigenetic modifications 5-methylcytosine and 5-hydroxymethylcytosine in DNA regulate neuronal survival under ischemic stress. We previously showed that TET3 (ten-eleven translocase 3)-mediated 5-methylcytosine to 5-hydroxymethylcytosine conversion induces neuroprotective gene transcription after stroke. As TET3 neuronal isoform lacks the DNA-binding domain, how TET3 drives 5-hydroxymethylcytosine-mediated transcriptional induction in the ischemic brain remains unclear. Long noncoding RNAs (lncRNAs) act as structural scaffolds to recruit chromatin-modifying proteins and other RNAs to specific genomic loci. However, whether TET3 requires an lncRNA to drive DNA hydroxymethylation in the ischemic brain is unknown. METHODS: Adult male and female mice were subjected to transient middle cerebral artery occlusion. TET3-bound lncRNAs were immunoprecipitated from peri-infarct cortex, and TILR (TET3-interacting lncRNA; AK020504) identified was inhibited with small interfering RNA injected at 5 minutes of reperfusion. Ascorbate was administered at 30 minutes of reperfusion to induce TET3 activity. Poststroke DNA hydroxymethylation was assessed with hydroxymethylation DNA immunoprecipitation sequencing, and sensorimotor deficits, and infarct volume were evaluated between days 1 and 7 of reperfusion. RESULTS: TILR binds to TET3 with high affinity and was significantly upregulated in the peri-infarct cortex at 12 hours of reperfusion. Knockdown of TILR increased the infarct volume and reduced the motor function recovery after transient middle cerebral artery occlusion, in a TET3-dependent manner. On contrary, TET3 activation by ascorbate decreased brain damage and improved motor function recovery after ischemia. However, ascorbate-induced postischemic protection was abrogated by TILR knockdown. Genome-wide profiling showed that ascorbate increases the number of differentially hydroxymethylated regions in the poststroke genome, a neuroprotective effect that is reversed by TILR knockdown. Moreover, TILR inhibition significantly reduced the DNA hydroxymethylation in the intergenic regions associated with enhancers, super enhancers, and the promoters of other lncRNAs, microRNAs, and PIWI-interacting RNAs. CONCLUSIONS: These findings highlight the essential role of TILR in TET3-mediated 5-hydroxymethylcytosine-dependent epigenetic reprogramming in the ischemic brain.

  PublisherDOI

• LONG NONCODING RNA INTERACTION IS ESSENTIAL FOR EPIGENETIC MODULATION OF ISCHEMIC BRAIN DAMAGE

  IBRO Neuroscience Reports · 2023-10-01

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Abstract WP236: Tet3 Overexpression Improves Functional Recovery In Male And Female Mice Following Focal Ischemia

  Stroke · 2023-02-01

  articleSenior author

  Epigenetic mechanisms have been shown to play a major role in the progression of stroke pathophysiology. The ten eleven translocases (TETs) are enzymes involved in generating DNA hydroxymethylcytosine (5hmC), a brain enriched epigenetic modification that is associated with transcriptional activation and neuroprotection. We have previously shown that the TET3 isoform may be involved in promoting endogenous neuroprotective pathways following brain injury. In the current study, we investigated the role of TET3 activity after stroke by examining functional recovery, neuroprotection, and sex-specific differences after TET3 modulation. Adult C57BL6/J mice were subjected to transient middle cerebral artery occlusion (MCAO) to induce focal cerebral ischemia. Dot blotting analysis revealed robust induction of 5hmC levels from 1 hour to 24 hours of reperfusion in the mouse cortex. Intracerebral injection of a neuronal-specific TET3 adenovirus further enhanced TET activity and 5hmC levels in both male and female mice. Overexpression of TET3 led to decreased infarct volume and edema and improved neurological scores at 24 hours of reperfusion. Furthermore, both male and female mice subjected to a battery of motor function assessments from 3 days to 14 days of reperfusion displayed enhanced motor function recovery with increased TET3. These results indicate that TET3-mediated epigenetic regulation may hold therapeutic potential following cerebral ischemia.

  PublisherDOI

• Post-stroke brain can be protected by modulating the lncRNA FosDT

  Journal of Cerebral Blood Flow & Metabolism · 2023-11-07 · 18 citations

  articleOpen access

  We previously showed that knockdown or deletion of Fos downstream transcript (FosDT; a stroke-induced brain-specific long noncoding RNA) is neuroprotective. We presently tested the therapeutic potential of FosDT siRNA in rodents subjected to transient middle cerebral artery occlusion (MCAO) using the Stroke Treatment Academic Industry Roundtable criteria, including sex, age, species, and comorbidity. FosDT siRNA (IV) given at 30 min of reperfusion significantly improved motor function recovery (rotarod test, beam walk test, and adhesive removal test) and reduced infarct size in adult and aged spontaneously hypertensive rats of both sexes. FosDT siRNA administered in a delayed fashion (3.5 h of reperfusion following 1 h transient MCAO) also significantly improved motor function recovery and decreased infarct volume. Furthermore, FosDT siRNA enhanced post-stroke functional recovery in normal and diabetic mice. Mechanistically, FosDT triggered post-ischemic neuronal damage via the transcription factor REST as REST siRNA mitigated the enhanced functional outcome in FosDT −/− rats. Additionally, NF-κB regulated FosDT expression as NF-κB inhibitor BAY 11-7082 significantly decreased post-ischemic FosDT induction. Thus, FosDT is a promising target with a favorable therapeutic window to mitigate secondary brain damage and facilitate recovery after stroke regardless of sex, age, species, and comorbidity.

  PublisherOA PDFDOI

• Abstract TP233: Cerebroprotective Role Of M ⁶ A Demethylase Fat Mass And Obesity-associated Protein After Experimental Stroke

  Stroke · 2023-02-01

  article

  Fat mass and obesity-associated protein (FTO) demethylates N 6 -methyladenosine (m 6 A), which is a critical epitranscriptomic regulator of neuronal function. We previously reported that ischemic stroke induces m 6 A hypermethylation with a simultaneous decrease in FTO expression in the neurons. Currently, we evaluated the functional significance of restoring FTO with an adeno-associated virus 9 (AAV9), and thus reducing m 6 A methylation in the post-stroke brain damage. Adult male and female C57BL/6J mice were injected with FTO AAV9 (intracerebral) at 21 days prior to inducing transient middle cerebral artery occlusion. Post-stroke brain damage (infarction, atrophy and white matter integrity) and neurobehavioral deficits (motor function, cognition, depression and anxiety-like behaviors) were evaluated between days 1 and 28 of reperfusion. FTO overexpression significantly decreased the post-stroke m 6 A hypermethylation. More importantly, exogenous FTO substantially decreased post-stroke grey and white matter damage and improved motor function recovery, cognition and depression-like behavior in both sexes. These results demonstrate that FTO-dependent m 6 A demethylation minimizes long-term sequelae of stroke independent of sex.

  PublisherDOI

• Epigenetic mechanisms and potential therapeutic targets in stroke

  Journal of Cerebral Blood Flow & Metabolism · 2022-07-19 · 36 citations

  reviewOpen access1st author

  Accumulating evidence indicates a central role for epigenetic modifications in the progression of stroke pathology. These epigenetic mechanisms are involved in complex and dynamic processes that modulate post-stroke gene expression, cellular injury response, motor function, and cognitive ability. Despite decades of research, stroke continues to be classified as a leading cause of death and disability worldwide with limited clinical interventions. Thus, technological advances in the field of epigenetics may provide innovative targets to develop new stroke therapies. This review presents the evidence on the impact of epigenomic readers, writers, and erasers in both ischemic and hemorrhagic stroke pathophysiology. We specifically explore the role of DNA methylation, DNA hydroxymethylation, histone modifications, and epigenomic regulation by long non-coding RNAs in modulating gene expression and functional outcome after stroke. Furthermore, we highlight promising pharmacological approaches and biomarkers in relation to epigenetics for translational therapeutic applications.

  PublisherOA PDFDOI

• High-Dose Vitamin C Prevents Secondary Brain Damage After Stroke via Epigenetic Reprogramming of Neuroprotective Genes

  Translational Stroke Research · 2022-03-20 · 32 citations

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• An Antioxidant and Anti-ER Stress Combo Therapy Decreases Inflammation, Secondary Brain Damage and Promotes Neurological Recovery following Traumatic Brain Injury in Mice

  Journal of Neuroscience · 2022-07-26 · 19 citations

  articleOpen access

  The complex pathophysiology of post-traumatic brain damage might need a polypharmacological strategy with a combination of drugs that target multiple, synergistic mechanisms. We currently tested a combination of apocynin (curtails formation of reactive oxygen species), tert-butylhydroquinone (promotes disposal of reactive oxygen species), and salubrinal (prevents endoplasmic reticulum stress) following a moderate traumatic brain injury (TBI) induced by controlled cortical impact in adult mice. Adult mice of both sexes treated with the above tri-combo showed alleviated motor and cognitive deficits, attenuated secondary lesion volume, and decreased oxidative DNA damage. Concomitantly, tri-combo treatment regulated post-TBI inflammatory response by decreasing the infiltration of T cells and neutrophils and activation of microglia in both sexes. Interestingly, sexual dimorphism was seen in the case of TBI-induced microgliosis and infiltration of macrophages in the tri-combo-treated mice. Moreover, the tri-combo treatment prevented TBI-induced white matter volume loss in both sexes. The beneficial effects of tri-combo treatment were long-lasting and were also seen in aged mice. Thus, the present study supports the tri-combo treatment to curtail oxidative stress and endoplasmic reticulum stress concomitantly as a therapeutic strategy to improve TBI outcomes.

  PublisherOA PDFDOI

• Cerebroprotective Role of <i>N</i> ⁶ -Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) After Experimental Stroke

  Stroke · 2022-11-02 · 41 citations

  articleOpen access

  Background: FTO (fat mass and obesity-associated protein) demethylates N 6 -methyladenosine (m 6 A), which is a critical epitranscriptomic regulator of neuronal function. We previously reported that ischemic stroke induces m 6 A hypermethylation with a simultaneous decrease in FTO expression in neurons. Currently, we evaluated the functional significance of restoring FTO with an adeno-associated virus 9, and thus reducing m 6 A methylation in poststroke brain damage. Methods: Adult male and female C57BL/6J mice were injected with FTO adeno-associated virus 9 (intracerebral) at 21 days prior to inducing transient middle cerebral artery occlusion. Poststroke brain damage (infarction, atrophy, and white matter integrity) and neurobehavioral deficits (motor function, cognition, depression, and anxiety-like behaviors) were evaluated between days 1 and 28 of reperfusion. Results: FTO overexpression significantly decreased the poststroke m 6 A hypermethylation. More importantly, exogenous FTO substantially decreased poststroke gray and white matter damage and improved motor function recovery, cognition, and depression-like behavior in both sexes. Conclusions: These results demonstrate that FTO-dependent m 6 A demethylation minimizes long-term sequelae of stroke independent of sex.

  PublisherOA PDFDOI

• Tenascin-C induction exacerbates post-stroke brain damage

  Journal of Cerebral Blood Flow & Metabolism · 2021-10-25 · 25 citations

  articleOpen access

  The role of tenascin-C (TNC) in ischemic stroke pathology is not known despite its prognostic association with cerebrovascular diseases. Here, we investigated the effect of TNC knockdown on post-stroke brain damage and its putative mechanism of action in adult mice of both sexes. Male and female C57BL/6 mice were subjected to transient middle cerebral artery occlusion and injected (i.v.) with either TNC siRNA or a negative (non-targeting) siRNA at 5 min after reperfusion. Motor function (beam walk and rotarod tests) was assessed between days 1 and 14 of reperfusion. Infarct volume (T2-MRI), BBB damage (T1-MRI with contrast), and inflammatory markers were measured at 3 days of reperfusion. The TNC siRNA treated cohort showed significantly curtailed post-stroke TNC protein expression, motor dysfunction, infarction, BBB damage, and inflammation compared to the sex-matched negative siRNA treated cohort. These results demonstrate that the induction of TNC during the acute period after stroke might be a mediator of post-ischemic inflammation and secondary brain damage independent of sex.

  PublisherOA PDFDOI

Frequent coauthors

• Raghu Vemuganti

  Neurological Surgery

  76 shared

• Anil K. Chokkalla

  Baylor College of Medicine

  46 shared

• Suresh L. Mehta

  Neurological Surgery

  30 shared

• Mario J. Bertogliat

  University of Minnesota

  25 shared

• Saivenkateshkomal Bathula

  University of Wisconsin–Madison

  23 shared

• Bharath Chelluboina

  University of Wisconsin System

  23 shared

• TaeHee Kim

  Neurological Surgery

  22 shared

• Raghu Vemuganti

  William S. Middleton Memorial Veterans Hospital

  21 shared