A. Personal Statement

I am a highly motivated and accomplished scientist specializing in stem cell research, genomics, molecular biology, and neuroscience. My research focuses on understanding the genetic and molecular mechanisms underlying neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer’s disease, using genetic approaches and human stem cell models. Currently, I am a postdoctoral fellow at NorthShore University HealthSystem Research Institute, where I have been conducting cutting-edge research for the past four years.

With 12 publications and 741 citations, my research has significantly impacted the field of neuroscience. I have presented my work at prestigious conferences, received multiple awards, and served as a reviewer for top journals. My expertise in chromatin accessibility profiling, gene regulation, induced pluripotent stem cell (iPSC) models, and neurodevelopmental disease mechanisms makes me well-suited to lead and contribute to projects at the intersection of genetics, neuroscience, and precision medicine.

My goal is to advance our understanding of the genetic basis of neurological diseases and translate these findings into potential therapeutic interventions. My diverse research background, strong analytical skills, and experience in functional genomics will contribute to the success of this project.

B. Positions, Scientific Appointments, and Honors

Positions and Scientific Appointments

2024-Present  Postdoctoral Fellow, National Health Data Science Lab, Tysons, VA

2018-Present  Postdoctoral Fellow, NorthShore University HealthSystem, Evanston, IL

2011-2017 Graduate Researcher, University of Illinois at Chicago, IL

2008-2011  Research Assistant, University of Chicago, Chicago, IL

2005-2008 Research Assistant, Russian Academy of Sciences, Moscow, Russia

Honors and Awards

2018                        Reviewer Choice Abstract Award, ASHG Meeting, San Diego, CA

2013, 2016              Graduate College Student Presenter Award, UIC, Chicago, IL

2013, 2016          PhD Student Travel Award, UIC, Chicago, IL

2016                        Graduate Student Council Travel Award, UIC, Chicago, IL

2013, 2015, 2016    Department of Biological Sciences Travel Award, UIC, Chicago, IL

Journal Peer Review Service

Scientific Reports (2 manuscripts)

С. Research Contribution and Accomplishments

1.      My early publications used methylation-sensitive high resolution melting analysis to assess methylation of CpG islands within the TIMP4, GATA4, SOX18, and EGFL7 genes in samples of non–small cell lung cancer and surrounding apparently normal tissue and noncancerous lung tissues. I found that the promoter methylation was heterogeneous in both tumor and surrounding normal tissue. This contrasts with healthy lung tissue, where the promoters were normally either non- or hypomethylated, and the heterogeneity of methylation was low. My findings suggested that an increased heterogeneity of methylation in the normal tissues surrounding the tumor may is an early start of epigenetic processes preceding genetic and morphologic changes and can be used as a biomarker of early cancerization events. My work led to the invention of an easy and sensitive tool for studying epigenetic heterogeneity and could be used in clinical practice.

a.     Azhikina T, Kozlova A, Skvortsov T, Sverdlov E. Heterogeneity and degree of TIMP4, GATA4, SOX18, and EGFL7 gene promoter methylation in non-small cell lung cancer and surrounding tissues. Cancer Genet. 2011 Sep; 204(9):492-500. PMID: 22018271.

2.          I also studied the relation of microbiota and viral infection. To establish chronic infections, viruses must develop strategies to evade the host’s immune responses. Many retroviruses, including mouse mammary tumor virus (MMTV), are transmitted most efficiently through mucosal surfaces rich in microbiota. I found that MMTV, when ingested by newborn mice, stimulates a state of unresponsiveness toward viral antigens. This process requires intestinal microbiota. MMTV-bound bacterial lipopolysaccharide triggered Toll-like receptor 4 and subsequent interleukin-6 (IL-6)–dependent induction of the inhibitory cytokine IL-10. Thus, MMTV has evolved to rely on the interaction with the microbiota to induce an immune evasion pathway. Together, my findings reveal the fundamental importance of commensal microbiota in viral infections.

a. Kane M, Case LK, Kopaskie K, Kozlova A, MacDearmid C, Chervonsky AV, Golovkina TV. Successful transmission of a retrovirus depends on the commensal microbiota. Science. 2011 Oct; 14;334(6053):245-9. PMID: 21998394.

3.     Microglia are the primary innate immune cell type in the brain that have been implicated in the pathogenesis of several neurodegenerative and neuropsychiatric disorders, most notably Alzheimer's disease and schizophrenia. Microglia generated from human induced pluripotent stem cells (hiPSCs) represent a promising in vitro cellular model for studying the neuroimmune interactions involved in these disorders. I generated iMG that morphologically and functionally resembled microglia. These iMG cells were found to be transcriptionally similar to previously reported iMG, as well as fetal and adult microglia. Furthermore, by using cell type-specific gene expression to partition disease heritability, I showed that iMG cells are genetically relevant to Alzheimer's disease. Across a range of neuronal and immune cell types, only iMG, primary microglia, and microglia-like cell types exhibited significant enrichment for Alzheimer's disease heritability. My results support the use of iMG as a human cellular model for understanding Alzheimer's disease biology and underlying genetic factors, as well as for developing and efficiently screening new therapeutics.

a.     Butler Iii RR, Kozlova A, Zhang H, Zhang S, Streit M, Sanders AR, Laudanski K, Pang ZP, Gejman PV, Duan J. The Genetic Relevance of Human Induced Pluripotent Stem Cell-Derived Microglia to Alzheimer's Disease and Major Neuropsychiatric Disorders. Mol Neuropsychiatry. 2020 Apr;5(Suppl 1):85-96. doi: 10.1159/000501935. Epub 2019 Jul 23. PMID: 32399472.

4.          Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, it was reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. I participated in the research where thousands of genetic variants exhibiting allele-specific open chromatin (ASoC) were identified using human induced pluripotent stem cell (iPSC)–derived neurons that model developing brains. ASoCs were found to be enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. My study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.

a.     Zhang S, Zhang H, Zhou Y, Qiao M, Zhao S, Kozlova A, Shi J, Sanders AR, Wang G, Luo K, Sengupta S, West S, Qian S, Streit M, Avramopoulos D, Cowan CA, Chen M, Pang ZP, Gejman PV, He X, Duan J. Allele-specific open chromatin in human iPSC neurons elucidates functional disease variants. Science. 2020 Jul 31;369(6503):561-565. doi: 10.1126/science.aay3983. PMID: 32732423.

5.     Identifying causative gene(s) within disease-associated large genomic regions is challenging. I identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in schizophrenia (SZ) cases. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, I modeled the OTUD7A LoF mutation in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs). I showed that the mutant iNs showed a ∼50% decrease in OTUD7A expression, exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function and was associated with SZ and other neuropsychiatric disorders. My results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.

a.     Kozlova A, Zhang S, Kotlar AV, Jamison B, Zhang H, Shi S, Forrest MP, McDaid J, Cutler DJ, Epstein MP, Zwick ME, Pang ZP, Sanders AR, Warren ST, Gejman PV, Mulle JG, Duan J. Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons. Am J Hum Genet. 2022 Aug 4;109(8):1500-1519. doi: 10.1016/j.ajhg.2022.07.001. PMID: 35931052.

6.        The mechanistic tie between genome-wide association study (GWAS)-implicated risk variants and disease-relevant cellular phenotypes remains largely unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons as a neurodevelopmental model, I participated in the research to identify multiple schizophrenia (SZ) risk variants that display allele-specific open chromatin (ASoC) and are likely to be functional. Editing the strongest ASoC SNP rs2027349, near vacuolar protein sorting 45 homolog (VPS45) alters the expression of VPS45, IncRNA AC244033.2, and a distal gene, C1orf54. Notably, the transcriptomic changes in neurons are associated with SZ and other neuropsychiatric disorders. Neurons carrying the risk allele exhibit increased dendritic complexity and hyperactivity. Interestingly, individual/combinatorial gene knockdown shows that these genes alter cellular phenotypes in a non-additive synergistic manner. My study reveals that multiple genes at a single GWAS risk locus mediate a compound effect on neural function, providing a mechanistic link between a non-coding risk variant and disease-related cellular phenotypes.

a.     Zhang S, Zhang H, Forrest MP, Zhou Y, Sun X, Bagchi VA, Kozlova A, Santos MD, Piguel NH, Dionisio LE, Sanders AR, Pang ZP, He X, Penzes P, Duan J. Multiple genes in a single GWAS risk locus synergistically mediate aberrant synaptic development and function in human neurons. Cell Genom. 2023 Aug 28;3(9):100399. doi: 10.1016/j.xgen.2023.100399. PMID: 37719141; PMCID: PMC10504676.

7.          Despite genome-wide association studies of late-onset Alzheimer’s disease (LOAD) having identified many genetic risk loci1–6, the underlying disease mechanisms remain largely unknown. Determining causal disease variants and their LOAD-relevant cellular phenotypes have been a challenge. Leveraging our approach for identifying functional GWAS risk variants showing allele-specific open chromatin (ASoC)7, I systematically identified putative causal LOAD risk variants in human induced pluripotent stem cells (iPSC)-derived neurons, astrocytes, and microglia (MG) and linked PICALM risk allele to a previously unappreciated MG-specific role of PICALM in lipid droplet (LD) accumulation. ASoC mapping uncovered functional risk variants for 26 LOAD risk loci, mostly MG-specific. At the MG-specific PICALM locus, the LOAD risk allele of rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aβ) and myelin debris. Interestingly, MG with PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of MG further established a causal link between the reduced PICALM expression, LD accumulation, and phagocytosis deficits. My work elucidates the selective LOAD vulnerability in microglia for the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing novel clinical interventions.

a.     Kozlova A, Zhang S, Sudwarts A, Zhang H, Smirnou S, Sun X, Stephenson K, Zhao X, Jamison B, Ponnusamy M, He X, Pang ZP, Sanders AR, Bellen HJ, Thinakaran G, Duan J. Alzheimer's disease risk allele of PICALM causes detrimental lipid droplets in microglia. Res Sq [Preprint]. 2024 May 24:rs.3.rs-4407146. doi: 10.21203/rs.3.rs-4407146/v1. PMID: 38826437; PMCID: PMC11142308.