Ilker K. Sariyer, DVM, PhD

Research Interests

My research has focused on understanding the molecular regulation of alternative premRNA splicing and RNA editing in normal as well as pathologic conditions associated with neuronal degenerative disorders and neurotropic viral infections. Some of these include Progressive Multifocal Leukoencephalopathy (PML), Neuro-HIV, and behavioral and physical conditions caused by addictive substances (including alcohol and opioids). Current projects are summarized below:

Alternative pre-mRNA splicing and Fetal Alcohol Syndrome (FAS): Ethanol consumption can modulate not only the level of transcription of multiple genes, but also the ratio of their spliced variants. Little is known about the role of alcohol in alternative splicing of cellular genes. We were the first to discover that ethanol exposure can lead to pre-mRNA missplicing of Mcl-1, a pro-survival member of the Bcl-2 family, by downregulating the expression levels of serine/arginine rich splicing factor 1 (SRSF1). Little was known about the physiological expression of these isoforms in neuronal cells and their role in toxicity induced by alcohol exposure during the developmental period. In order to investigate the impact of alcohol exposure on alternative splicing of Mcl-1 pre-mRNA and its role in neurotoxicity, we developed a unique primary human neuronal culture model where neurospheres (hNSPs), neural progenitors (hNPCs), immature neurons, and mature neurons were cultured from the matching donor fetal brain tissues. Our data suggested that neural progenitors and immature neurons were highly sensitive to the toxic effects of ethanol, while mature neuron cultures showed resistance to ethanol exposure. Interestingly, ectopic expression of Mcl-1L isoform in neural progenitors was able to recover the viability loss and apoptosis induced by alcohol exposure. Altogether, our observations suggested that alternative splicing of pro-survival factors may play a crucial role in neurotoxicity associated with alcohol exposure in the developing fetal brain.

Alternative pre-mRNA splicing and opioid dependence: Clinically used opioids, such as morphine, activate OPRM1, a member of the G protein-coupled receptor (GPCR) family. Examination of the opioid receptor genes showed that the OPRM1 gene undergoes extensive alternative splicing events. To date, 21 isoforms of the human OPRM1 have been identified. However, characterization of OPRM1 signaling is generalized, and only one isoform (MOR-1) has been extensively studied. Compounding this issue is the increasing significance of intravenous drug abuse in HIV neuropathogenesis. Multiple studies have shown that opioid abuse may potentiate HIV neurocognitive alterations indirectly or directly by stimulating overlapping signaling pathways in neurons. Our latest studies suggest that HIV-1 contributes to the enhanced rate of opioid dependence in HIV/AIDS patients by amplifying the rate of OPRM1 alternative splicing induced by morphine. Our current studies focus on understanding of the opioid dependence associated with alternative splicing of OPRM1 and possible mechanisms underlying enhanced development of opioid abuse and dependence observed in the people living with HIV/AIDS (PLWHA).

HIV-1 and neurological disorders: HIV-associated CNS dysfunction occurs in greater than 50% of people with HIV (PWH) and is a significant problem among individuals who live longer due to the combined anti-retroviral therapy (cART). HIV utilizes viral proteins and subsequent cytokine induction to unleash its toxicity on neurons. Among these viral proteins, HIV Nef is found in neurons of postmortem brain specimens from PWH, who suffered cognitive impairment. However, the source of neuronal Nef, mechanism of its uptake by neurons, and its impact on neuronal cell homeostasis are still elusive. Our recent research suggest that Nef protein is release in extracellular vesicles (EVs) from HIV-infected glia that mediates the neuronal uptake of Nef leading to the dysregulation of neuronal cell homeostasis. Our ongoing research focuses on defining the contribution of Nef-EVs to the development of HIV-associated CNS dysfunction and determine the mechanism(s) of neurotoxicity and neurophysiological defects associated with Nef-EVs.

JC Virus and PML: Patients undergoing immune modulatory therapies for the treatment of autoimmune diseases such as multiple sclerosis, and individuals with an impaired-immune system, most notably AIDS patients, are in the high-risk group of developing progressive multifocal leukoencephalopath (PML), a fatal demyelinating disease of the white matter caused by human neurotropic polyomavirus, JC virus. We employ multidisciplinary strategies to determine molecular mechanism of JC virus reactivation during the latent period of viral infection. We identified the alternative splicing factor, SF2/ASF, as a potential regulator of JCV as its overexpression in glial cells strongly suppresses viral gene expression and replication. In addition, a major effort in our laboratory is focused on biomarker potential of agnoprotein, a small regulatory protein of JC virus, for the early diagnosis and the prognosis of the PML.

Educational Background

• PhD, Biomedical Sciences, Temple University School of Medicine, Philadelphia, PA, 2011
   
• DVM, Selcuk University, School of Veterinary Medicine, Konya, Turkey, 2000

Digital Bibliography

View PubMed Publications