The overall objective of this proposal is to provide advanced training for the career development of Dr. Qing Ma, a clinical pharmacologist, in antiretroviral pharmacogenomics, pharmacokinetics and disease modeling in patients with HIV-associated neurocognitive disorders. Through research training, coursework and independent studies, he will develop collaborative relationship with his mentors and skills to achieve his long- term career goal to become an independent clinical investigator focusing on pharmacogenomics of antiretroviral therapy and neurocognitive disorders. He will be working in a rich environment under successful senior investigators from University at Buffalo (Dr. Gene Morse), Vanderbilt University (Dr. David Haas) and University of Rochester (Dr. Giovanni Schifitto). Specific areas of mentorship and training include pharmacogenomics, genetic analysis and bioinformatics, population pharmacokinetic analysis and disease modeling. This proposal focuses on the genomic impact on antiretroviral pharmacokinetics, response and toxicity in patients with HIV-associated neurocognitive disorders (HAND), one of the most prevalent co- morbidities in treated individuals. To achieve this immediate goal, patient samples and longitudinal data will be used from two well-characterized studies: CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and Clinical Trial of CNS Penetrating ART to Prevent NeuroAIDS in China. The risk for HAND may be related to limited distribution of antiretrovirals into the brain but the specific genetic factors associated with variations in brain exposure are largely unknown. Our central hypothesis is that genetic variants that are associated with antiretroviral pharmacokinetics and neurotoxicity will also be associated with HAND in treated individuals.
The specific aims of the proposed research are: 1) to determine the association between antiretroviral pharmacokinetics and neurocognitive function among treated patients from CHARTER and Chinese studies;2) to identify genes and genetic polymorphisms that are associated with antiretroviral exposure, particularly genes that are linked to drug metabolism and drug distribution into the central nervous system;3) to identify neurotoxicity and inflammation-associated genes that are linked to neurocognitive abnormalities using gene expression profiling and bioinformatics techniques;4) to develop a disease progression model that integrates pharmacokinetics and the genetic data generated from aims 1 to 3 to predict HAND development. The identification of genetic markers correlated with antiretroviral pharmacokinetics and neurocognitive function will shed lights on HAND etiology and will provide patients and clinicians a useful tool for intervention and risk assessment on an individualized basis. The proposed training and research activities will provide Dr. Qing Ma a foundation that he can generate competitive grant applications in the final years of the award and advance patient care through personalized medicine.
The overall objective of this proposal is to provide advanced training for the career development of Dr. Qing Ma, in antiretroviral pharmacogenomics, pharmacokinetics and disease modeling in patients with HIV-associated neurocognitive disorders. The research plan focuses on the development of a model system to improve risk and intervention assessments by integrating genetic data, pharmacokinetics and toxicity to establish an individualized risk profile of HIV-associated neurocognitive disorders, one of the prevalent co-morbidities in treated individuals.
|Ocque, Andrew J; Hagler, Colleen E; Morse, Gene D et al. (2018) Development and validation of an LC-MS/MS assay for tenofovir and tenofovir alafenamide in human plasma and cerebrospinal fluid. J Pharm Biomed Anal 156:163-169|
|Zhuang, Yuchuan; Qiu, Xing; Wang, Lu et al. (2017) Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals. J Neurovirol 23:704-712|
|Liu, Xia; Ma, Qing; Zhao, Yan et al. (2017) Impact of Single Nucleotide Polymorphisms on Plasma Concentrations of Efavirenz and Lopinavir/Ritonavir in Chinese Children Infected with the Human Immunodeficiency Virus. Pharmacotherapy 37:1073-1080|
|Adedeji, Waheed Adeola; Igbinoba, Sharon Iyobor; Fakeye, Titilayo O et al. (2017) Evaluation of CYP2D6 phenotype in the Yoruba Nigerian population. Expert Rev Clin Pharmacol 10:1145-1152|
|Bednasz, Cindy J; Venuto, Charles S; Ma, Qing et al. (2017) Efavirenz Therapeutic Range in HIV-1 Treatment-Naive Participants. Ther Drug Monit 39:596-603|
|Mollan, Katie R; Tierney, Camlin; Hellwege, Jacklyn N et al. (2017) Race/Ethnicity and the Pharmacogenetics of Reported Suicidality With Efavirenz Among Clinical Trials Participants. J Infect Dis 216:554-564|
|Bednasz, Cindy J; Venuto, Charles S; Ma, Qing et al. (2017) Pharmacokinetic Considerations for Combining Antiretroviral Therapy, Direct-Acting Antiviral Agents for Hepatitis C Virus, and Addiction Treatment Medications. Clin Pharmacol Drug Dev 6:135-139|
|Nwogu, Jacinta Nwamaka; Ma, Qing; Babalola, Chinedum Peace et al. (2016) Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals. AIDS Res Treat 2016:2587094|
|Bednasz, Cindy; Luque, Amneris E; Zingman, Barry S et al. (2016) Lipid-Lowering Therapy in HIV-Infected Patients: Relationship with Antiretroviral Agents and Impact of Substance-Related Disorders. Curr Vasc Pharmacol 14:280-7|
|Ma, Qing; Vaida, Florin; Wong, Jenna et al. (2016) Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol 22:170-8|
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