Bradley E. Aouizerat
Professor, College of Dentistry
Professor, College of Dentistry
Dental Center, 421 First Avenue
New York, NY 10010
Bradley E. Aouizerat's additional information
BS, Microbiology/ Molecular Genetics - University of California at Los AngelesPhD, Microbiology/ Molecular Genetics/lmmunology - University of California at Los AngelesMAS, Master of Advance Science Research in Clinical - University of California at San Francisco
American Heart AssociationAmerican Liver FoundationAmerican Pain SocietyAmerican Society for Human GeneticsInternational Association for the Study of Pain
Faculty Honors AwardsExcellence in Research Mentoring Faculty Teaching Award (2013)Excellence in Research Mentoring Faculty Teaching Award (Nominee) (2012)Excellence in Research Mentoring Faculty Teaching Award (Nominee) (2011)Most Dedicated Mentor Award, PMCTR Fellowship Program (2009)Multidisciplinary Clinical Research Scholar, Roadmap K12 (2006)Early Career Investigator Award, Bayer Healthcare International (2006)Young Investigator Award, National Hemophilia Foundation (2005)Early Career Faculty Award, Hellman Family (2005)Faculty Mentorship Award Nominee (2005)Faculty Mentorship Award Nominee (2004)National Liver Scholar Award, American Liver Foundation (2004)Irvine H. Page Young Investigator Award (Finalist), American Heart Association (2004)Warsaw Fellowship (1998)Sam and Rose Gilbert Fellowship, UCLA (1998)
Circulating microRNAs associated with prediabetes and geographic location in LatinosAbstractFlowers, E., Ramírez-Mares, J. D., Velazquez-Villafaña, M., Rangel-Salazar, R., Sucher, A., Kanaya, A. M., Aouizerat, B. E., & De La Vega Monroy, M. L. L. (2021). International Journal of Diabetes in Developing Countries. 10.1007/s13410-020-00917-1AbstractBackground: Globally, type 2 diabetes is highly prevalent in individuals of Latino ancestry. The reasons underlying this high prevalence are not well understood, but both genetic and lifestyle factors are contributors. Circulating microRNAs are readily detectable in blood and are promising biomarkers to characterize biological responses (i.e., changes in gene expression) to lifestyle factors. Prior studies identified relationships between circulating microRNAs and risk for type 2 diabetes, but Latinos have largely been under-represented in these study samples. Aims/hypothesis: The aim of this study was to assess for differences in expression levels of three candidate microRNAs (miR-126, miR-146, miR-15) between individuals who had prediabetes compared to normal glycemic status and between individuals who self-identified with Latino ancestry in the United States (US) and native Mexicans living in or near Leon, Mexico. Methods: This was a cross-sectional study that included 45 Mexicans and 21 Latino participants from the US. Prediabetes was defined as fasting glucose 100–125 mg/dL or 2-h post-glucose challenge between 140 and 199 mg/dL. Expression levels of microRNAs from plasma were measured by qPCR. Linear and logistic regression models were used to assess relationships between individual microRNAs and glycemic status or geographic site. Results: None of the three microRNAs was associated with risk for type 2 diabetes. MiR-146a and miR-15 were significantly lower in the study sample from Mexico compared to the US. There was a significant interaction between miR-146a and BMI associated with fasting blood glucose. Conclusions/interpretation: This study did not replicate in Latinos prior observations from other racial groups of associations between miR-126, miR-146a, and miR-15 and risk for type 2 diabetes. Future studies should consider other microRNAs related to different biological pathways as possible biomarkers for type 2 diabetes in Latinos.
Co-Occurrence of Symptoms and Gut Microbiota Composition Before Neoadjuvant Chemotherapy and Radiation Therapy for Rectal Cancer: A Proof of ConceptAbstractAbstractPurpose: To examine a) whether there are significant differences in gut microbial diversity and in the abundance of gut microbial taxa; and b) differences in predicted functional pathways of the gut microbiome between those participants with high co-occurring symptoms and those with low co-occurring symptoms, prior to neoadjuvant chemotherapy and radiation therapy (CRT) for rectal cancer. Methods: Rectal cancer patients (n = 41) provided stool samples for 16 S rRNA gene sequencing and symptom ratings for fatigue, sleep disturbance, and depressive symptoms prior to CRT. Descriptive statistics were computed for symptoms. Gut microbiome data were analyzed using QIIME2, LEfSe, and the R statistical package. Results: Participants with high co-occurring symptoms (n = 19) had significantly higher bacterial abundances of Ezakiella, Clostridium sensu stricto, Porphyromonas, Barnesiella, Coriobacteriales Incertae Sedis, Synergistiaceae, Echerichia-Shigella, and Turicibacter compared to those with low co-occurring symptoms before CRT (n = 22). Biosynthesis pathways for lipopolysaccharide, L-tryptophan, and colanic acid building blocks were enriched in participants with high co-occurring symptoms. Participants with low co-occurring symptoms showed enriched abundances of Enterococcus and Lachnospiraceae, as well as pathways for β-D-glucoronosides, hexuronide/hexuronate, and nicotinate degradation, methanogenesis, and L-lysine biosynthesis. Conclusion: A number of bacterial taxa and predicted functional pathways were differentially abundant in patients with high co-occurring symptoms compared to those with low co-occurring symptoms before CRT for rectal cancer. Detailed examination of bacterial taxa and pathways mediating co-occurring symptoms is warranted.
A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected womenAbstractMcIntosh, A. T., Wei, R., Ahn, J., Aouizerat, B. E., Kassaye, S. G., Augenbraun, M. H., Price, J. C., French, A. L., Gange, S. J., Anastos, K. M., & Goldman, R. (2021). PloS One, 16(3). 10.1371/journal.pone.0247277AbstractHIV coinfection is associated with more rapid liver fibrosis progression in hepatitis C (HCV) infection. Recently, much work has been done to improve outcomes of liver disease and to identify targets for pharmacological intervention in coinfected patients. In this study, we analyzed clinical data of 1,858 participants from the Women’s Interagency HIV Study (WIHS) to characterize risk factors associated with changes in the APRI and FIB-4 surrogate measurements for advanced fibrosis. We assessed 887 non-synonymous single nucleotide variants (nsSNV) in a subset of 661 coinfected participants for genetic associations with changes in liver fibrosis risk. The variants utilized produced amino acid substitutions that either altered an N-linked glycosylation (NxS/T) sequon or mapped to a gene related to glycosylation processes. Seven variants were associated with an increased likelihood of liver fibrosis. The most common variant, ALPK2 rs3809973, was associated with liver fibrosis in HIV/HCV coinfected patients; individuals homozygous for the rare C allele displayed elevated APRI (0.61, 95% CI, 0.334 to 0.875) and FIB-4 (0.74, 95% CI, 0.336 to 1.144) relative to those coinfected women without the variant. Although warranting replication, ALPK2 rs3809973 may show utility to detect individuals at increased risk for liver disease progression.
Model-Based Patterns of Lymphedema Symptomatology: Phenotypic and Biomarker CharacterizationAbstractAbstractPurpose of the Study: More than 50% of breast cancer survivors without a diagnosis of lymphedema suffer daily from numerous and co-occurring lymphedema symptoms. This study aimed to identify lymphedema symptom patterns and the association of such patterns with phenotypic characteristics and biomarkers using latent class analysis (LCA). A prospective, descriptive, and repeated-measure design was used to enroll 140 women and collect data. Recent Findings: LCA identified three distinct lymphedema symptom classes at 8 weeks and 12 months post-surgery: low, moderate, and severe symptom classes and associated phenotypic characteristics. Participants were more likely to be in the severe symptom classes at 12 months post-surgery if they had lower education level, cording, an axillary syndrome at 8 weeks post-surgery, neoadjuvant chemotherapy, and radiation. Summary: Pre-surgery level of IL1-a, IL-6, IL-8, and VEGF was associated with the severe symptom class at 8 weeks post-surgery, suggesting that such biomarkers may be used to predict risk for lymphedema symptoms.
TNFα promotes oral cancer growth, pain, and Schwann cell activationAbstractAbstractOral cancer is very painful and impairs a patient’s ability to eat, talk, and drink. Mediators secreted from oral cancer can excite and sensitize sensory neurons inducing pain. Cancer mediators can also activate Schwann cells, the peripheral glia that regulates neuronal function and repair. The contribution of Schwann cells to oral cancer pain is unclear. We hypothesize that the oral cancer mediator TNFα activates Schwann cells, which further promotes cancer progression and pain. We demonstrate that TNFα is overexpressed in human oral cancer tissues and correlates with increased self-reported pain in patients. Antagonizing TNFα reduces oral cancer proliferation, cytokine production, and nociception in mice with oral cancer. Oral cancer or TNFα alone increases Schwann cell activation (measured by Schwann cell proliferation, migration, and activation markers), which can be inhibited by neutralizing TNFα. Cancer- or TNFα-activated Schwann cells release pro-nociceptive mediators such as TNFα and nerve growth factor (NGF). Activated Schwann cells induce nociceptive behaviors in mice, which is alleviated by blocking TNFα. Our study suggests that TNFα promotes cancer proliferation, progression, and nociception at least partially by activating Schwann cells. Inhibiting TNFα or Schwann cell activation might serve as therapeutic approaches for the treatment of oral cancer and associated pain.
African Mitochondrial DNA Haplogroup L2 Is Associated with Slower Decline of β-cell Function and Lower Incidence of Diabetes Mellitus in Non-Hispanic, Black Women Living with Human Immunodeficiency VirusAbstractSun, J., Brown, T. T., Tong, W., Samuels, D., Tien, P., Aissani, B., Aouizerat, B., Villacres, M., Kuniholm, M. H., Gustafson, D., Michel, K., Cohen, M., Schneider, M., Adimora, A. A., Ali, M. K., Bolivar, H., & Hulgan, T. (2020). Clinical Infectious Diseases, 71(8), E218-E225. 10.1093/cid/ciaa026AbstractBackground: Susceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with human immunodeficiency virus (HIV; PLWH), but remains unexplored in populations with African ancestry. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and the homeostatic model assessments of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), as well as incident diabetes mellitus (DM), among Black women living with or at risk for HIV. Methods: Women without DM who had fasting glucose (FG) and insulin (FI) data for ≥2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI data. Incident DM was defined by a combination of FG ≥ 126 mg/dL, the use of DM medication, a DM diagnosis, or hemoglobin A1c ≥ 6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the associations between HOMA-B and HOMA-IR and DM by haplogroup. Results: Of 1288 women (933 living with HIV and 355 living without HIV), PLWH had higher initial HOMA-B and HOMA-IR than people living without HIV. PLWH with haplogroup L2 had a slower decline in HOMA-B per year (Pinteraction =. 02) and a lower risk of incident DM (hazard ratio [HR], 0.51; 95% confidence interval [CI],. 32-.82) than PLWH with other haplogroups after adjustments for age, body mass index, combination antiretroviral therapy use, CD4 cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2, compared to non-L2 (HR, 1.28 [95% CI,. 70-2.38] vs 4.13 [95% CI, 3.28-5.22], respectively; Pinteraction <. 01), among PLWH. Conclusions: Mitochondrial genetic variation is associated with β-cell functions and incident DM in non-Hispanic, Black women with HIV and alters the relationship between insulin resistance and DM.
Association of HLA genotype with T-cell activation in human immunodeficiency virus (HIV) and HIV/ hepatitis c virus-coinfected womenAbstractKovacs, A. A., Kono, N., Wang, C. H., Wang, D., Frederick, T., Operskalski, E., Tien, P. C., French, A. L., Minkoff, H., Kassaye, S., Golub, E. T., Aouizerat, B. E., Kuniholm, M. H., & Millstein, J. (2020). Journal of Infectious Diseases, 221(7), 1156-1166. 10.1093/infdis/jiz589AbstractBackground. Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus. Methods. We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10. Results. Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, −6.6% [P =.002]; CD4 T cells, −2.7% [P =.007]), C*18:01 (CD8 T cells, −6.6%; P <.0008) and DRB1*13:01 (CD4 T cells, −2.7%; P <.0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P <.0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03. Conclusion. These findings suggest that a person's HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.
Comparison of methylation capture sequencing and Infinium MethylationEPIC array in peripheral blood mononuclear cellsAbstractAbstractBackground: Epigenome-wide association studies (EWAS) have been widely applied to identify methylation CpG sites associated with human disease. To date, the Infinium MethylationEPIC array (EPIC) is commonly used for high-throughput DNA methylation profiling. However, the EPIC array covers only 30% of the human methylome. Methylation Capture bisulfite sequencing (MC-seq) captures target regions of methylome and has advantages of extensive coverage in the methylome at an affordable price. Methods: Epigenome-wide DNA methylation in four peripheral blood mononuclear cell samples was profiled by using SureSelectXT Methyl-Seq for MC-seq and EPIC platforms separately. CpG site-based reproducibility of MC-seq was assessed with DNA sample inputs ranging in quantity of high (> 1000 ng), medium (300–1000 ng), and low (150 ng–300 ng). To compare the performance of MC-seq and the EPIC arrays, we conducted a Pearson correlation and methylation value difference at each CpG site that was detected by both MC-seq and EPIC. We compared the percentage and counts in each CpG island and gene annotation between MC-seq and the EPIC array. Results: After quality control, an average of 3,708,550 CpG sites per sample were detected by MC-seq with DNA quantity > 1000 ng. Reproducibility of DNA methylation in MC-seq-detected CpG sites was high among samples with high, medium, and low DNA inputs (r > 0.96). The EPIC array captured an average of 846,464 CpG sites per sample. Compared with the EPIC array, MC-seq detected more CpGs in coding regions and CpG islands. Among the 472,540 CpG sites captured by both platforms, methylation of a majority of CpG sites was highly correlated in the same sample (r: 0.98–0.99). However, methylation for a small proportion of CpGs (N = 235) differed significantly between the two platforms, with differences in beta values of greater than 0.5. Conclusions: Our results show that MC-seq is an efficient and reliable platform for methylome profiling with a broader coverage of the methylome than the array-based platform. Although methylation measurements in majority of CpGs are highly correlated, a number of CpG sites show large discrepancy between the two platforms, which warrants further investigation and needs cautious interpretation.
Depression and psychosocial stress are associated with subclinical carotid atherosclerosis among women living with hivAbstractLevy, M. E., Anastos, K., Levine, S. R., Plankey, M., Castel, A. D., Molock, S., Sen, S., Asch, F. M., Milam, J., Aouizerat, B., Weber, K. M., Golub, E. T., Kaplan, R. C., & Kassaye, S. (2020). Journal of the American Heart Association, 9(13). 10.1161/JAHA.120.016425AbstractBACKGROUND: To identify reasons for increased atherosclerotic risk among women living with HIV (WLWH), we evaluated the associations between psychosocial risk factors (depressive symptoms, perceived stress, and posttraumatic stress disorder symptoms) and subclinical atherosclerosis among WLWH and HIV-negative women. METHODS AND RESULTS: Carotid artery focal plaque (localized intima-media thickness >1.5 mm) was measured using B-mode ultrasound imaging in 2004–2005 and 2010–2012 in the Women’s Interagency HIV Study. We created psychosocial risk groups using latent class analysis and defined prevalent plaque at the final measurement. We also examined repeated semiannual depression measures with respect to focal plaque formation throughout follow-up. The associations between latent class and prevalent plaque, and between depressive symptom persistence and plaque formation, were assessed separately by HIV status using multivariable logistic regression. Among 700 women (median age 47 years), 2 latent classes were identified: high (n=163) and low (n=537) psychosocial risk, with corresponding prevalence of depression (65%/13%), high stress (96%/12%), and probable posttraumatic stress disorder (46%/2%). Among WLWH, plaque prevalence was 23% and 11% in high versus low psychosocial risk classes (adjusted odds ratio [aOR], 2.12; 95% CI, 1.11–4.05) compared with 9% and 9% among HIV-negative women (aOR, 1.07; 95% CI, 0.24–4.84), respectively. New plaque formation occurred among 17% and 9% of WLWH who reported high depressive symptoms at ≥45% versus <45% of visits (aOR, 1.96; 95% CI, 1.06–3.64), compared with 9% and 7% among HIV-negative women (aOR, 0.82; 95% CI, 0.16–4.16), respectively. CONCLUSIONS: Psychosocial factors were independent atherosclerotic risk factors among WLWH. Research is needed to determine whether interventions for depression and psychosocial stress can mitigate the increased risk of atherosclerosis for WLWH.
A disintegrin and metalloproteinase domain 17-epidermal growth factor receptor signaling contributes to oral cancer painAbstractAbstractCancer cells secrete pronociceptive mediators that sensitize adjacent sensory neurons and cause pain. Identification and characterization of these mediators could pinpoint novel targets for cancer pain treatment. In this study, we identified candidate genes in cancer cell lines that encode for secreted or cell surface proteins that may drive nociception. To undertake this work, we used an acute cancer pain mouse model, transcriptomic analysis of publicly available human tumor-derived cell line data, and a literature review. Cancer cell line supernatants were assigned a phenotype based on evoked nociceptive behavior in an acute cancer pain mouse model. We compared gene expression data from nociceptive and nonnociceptive cell lines. Our analyses revealed differentially expressed genes and pathways; many of the identified genes were not previously associated with cancer pain signaling. Epidermal growth factor receptor (EGFR) and disintegrin metalloprotease domain 17 (ADAM17) were identified as potential targets among the differentially expressed genes. We found that the nociceptive cell lines contained significantly more ADAM17 protein in the cell culture supernatant compared to nonnociceptive cell lines. Cytoplasmic EGFR was present in almost all (>90%) tongue primary afferent neurons in mice. Monoclonal antibody against EGFR, cetuximab, inhibited cell line supernatant-induced nociceptive behavior in an acute oral cancer pain mouse model. We infer from these data that ADAM17-EGFR signaling is involved in cancer mediator-induced nociception. The differentially expressed genes and their secreted protein products may serve as candidate therapeutic targets for oral cancer pain and warrant further evaluation.