Digicaylioglu Lab

Principal Investigator: Murat Digicaylioglu MD
Research Focus: HIV Associated Dementia, Brain Tumors 

Mild cognitive decline that can lead to frank dementia is commonly associated with AIDS and known as HIV-associated neurocognitive disorder (or HAND).  Drug abuse, particularly with methamphetamine, is often encountered as a co-morbid condition in patients with HAND.  We utilize an innovative approach using newly emerging Mass Spectrometry (MS) techniques to identify modifications of proteins caused by free radical damage resulting from AIDS and drug abuse. This work will identify aberrant protein modifications effected by HAND and drug abuse, and thus new potential therapeutic targets as well as biomarkers of the disease process.

Astrocytomas are tumors of the brain and are divided into four grades. These tumors are also known as Glioblastoma Multiforme (GBM) and are extremely aggressive and refractory to chemotherapy and radiotherapy. Due to their malignancy, median survival of these tumors is limited to 14.6 to 24 months. There is no curative treatment available for GBM. Using disease and species specific models of GBM I am studying the metabolic activities in GBM to identify suitable therapeutic targets. A combination of metabolic starvation and the use of anti-angiogenic substances is promising. 


Selected Publications

  1. Designed, performed and analyzed experiments that characterized Erythropoietin binding sites in thalamus and cortex that were previously unknown. Further investigated the neuroprotective effects of Erythropoietin in mammal brain and identified novel crosstalk between two signaling pathways. These highly referenced publications significantly enhanced the research on neuroprotective potential of Erythropoietin by other scientists and biomedical companies
  2. Digicaylioglu, M. et al. (1995) Localization of specific erythropoietin binding sites in defined areas of the mouse brain. PNAS, 92,3717-3720.
  3. Marti, H. H. et al. (1996) Erythropoietin gene expression in human, monkey and murine brain. The

European journal of neuroscience, 8, 666-676.

  1. Digicaylioglu, M. & Lipton, S. A. (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature, 412, 641-647.
  2. Digicaylioglu, M., Kaul, M., Fletcher, L., Dowen, R. & Lipton, S. A. (2004) Erythropoietin protects cerebrocortical neurons from HIV-1/gp120-induced damage. Neuroreport,15, 761-763.
  3. Discovered and described a novel synergy between two neuroprotectants, Erythropoietin and Insulin-like growth factor I. This novel combination provided acute and chronic neuroprotection in ischemic stroke and also significantly reduced the dosing of either drug.
    1. Digicaylioglu, M., Garden, G., Timberlake, S., Fletcher, L. & Lipton, S. A. (2004) Acute neuroprotective synergy of erythropoietin and insulin-like growth factor I. PNAS, 101, 9855-9860.
    2. Fletcher, L. et al. (2009) Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation. J Neurosurgery, 111, 164-170.
    3. Kang, Y. J. et al. (2010) Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders. Annals of Neurology, 68, 342-352
  4. Discovered and described a specific form of intranasal delivery, the transcribrosal administration, that further enhances the potential for acute neuroprotection. Investigated the transcribrosal uptake mechanisms and identified the rostral migratory stream as the main path into the brain. I designed a prototype of an applicator for this delivery method (Patent pending, UT HSC San Antonio).
    1. Fletcher, L. et al. (2009) Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation. J Neurosurgery, 111, 164-170.
    2. Scranton, R. A., Fletcher, L., Sprague, S., Jimenez, D. F. & Digicaylioglu, M. (2011) The rostral migratory stream plays a key role in intranasal delivery of drugs into the CNS. PloS one, 6, e18711.
  5. Identified and described micro RNA’s that are likely to play a role in neurodegeneration and neurorestoration after stroke and acute spinal cord injury. The identified microRNA’s include miR-29b, miR-21, miR-30b, miR- 107 and miR-137.
    1. Ziu, M., Fletcher, L., Rana, S., Jimenez, D. F. & Digicaylioglu, M. (2011) Temporal differences in microRNA expression patterns in astrocytes and neurons after ischemic injury. PloS one, 6, e14724.
    2. Ziu, M. et al. (2014) Spatial and temporal expression levels of specific microRNAs in a spinal cord injury mouse model and their relationship to the duration of compression. The spine journal, 14, 353-360.
  6. Planned, conceived and executed the creation of a Shared Resource for Neurodegenerative Models at UT Health Science Center, San Antonio. The choice of animal models, the potential of the selected model for mimicking clinical presentation of a human disease and correct interpretation of the data are crucial for a productive and successful outcome of these experiments. Extensive training and appropriate setup of the surgical environment is essential to perform precise surgical procedures and exclude confounding factors. As a neurosurgeon I have generated protocols for surgical procedures and proper preoperative and postoperative care of models animal in accordance with IACUC rules. I have trained numerous technicians and NIH-funded scientists and provided over 5000 ischemic stroke, traumatic brain injury and spinal cord injury models to the scientific community. I have performed precise stereotaxic injections in selected brain areas of either drugs or cells and implanted devices into the CNS in over 1000 animals.
    1. Brochure describing the services provided by the Shared Resource for Neurodegenerative Models
    2. http://neurosurgery.uthscsa.edu/display.php?ps_id=55&pg=research.php (currently administered by Dr. Sayre)

In addition to basic science described in personal statement, translational research efforts by my group and collaborations with clinical and non-clinical scientists led to following achievements:

-Liposome delivered Renium 186 treatment for glioblastomas (Inventor: Dr. Brenner): Designed study concept for translational application and human administration (catheter size, craniectomy vs. craniotomy, application paramenter such as pressure, volume and duration) and co-wrote IND application with Drs.

Brenner and Floyd. Co-wrote the approved grant application by CTRC, study design for Clinical trial NCT01906385 (PI: Dr. Andrew Brenner).

-Development and clinical testing of compounds to treat traumatic brain injury: Helped to develop compounds 2-methylthio-ADP and MRS2365 (inventor: JC Lechleiter, Patent # 8,618,074) in in vitro human brain tissue (preclinical studies, toxicity testing), designing criteria for patient inclusion (only mild traumatic brain injury) and exclusion, prepared IND application with FDA, designed PD/PK protocols.

-EPODURE™ for sustained production and delivery of Erythropoietin (Phase I/II, Medgenics): As a medical consultant developed preclinical protocols, supported IND administration, participated in study design for Phase I, co-designed surgical implantation method for Biopump™ in brain and spinal cord.

-Role of PDK-1 and PDK-2 in suppression of malignant neurotumors: Identified PDK-1 inhibitors as potent modulators for mTOR suppression in human gliomas. Designed novel inhibitors and tested in human astrocytes in vitro, with promising outcome.

 

Complete List of Published Work in MyBibliography (2626 citations, h-Index 18) http://www.ncbi.nlm.nih.gov/sites/myncbi/1niDwc5NkvvA_/bibliography/50116452/public/?sort=date&direction=ascending.

 

 


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