Jinying Zhao

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Alzheimer's and Dementia
• Developmental Cognitive Neuroscience
• Cognitive Aging
• Learning and Memory

Active NIH awards

• Transcriptome-wide mapping of brain m6A methylome in Alzheimer’s disease

  1R01AG095602-01

  NIA · FY 2025 · $848K

  Alzheimer’s disease (AD) affects over 55 million people worldwide, and this number is expected to nearly triple by 2050. AD is characterized clinically by progressive cognitive decline, and pathologically by amyloid plaques, neurofibrillary tangles, and loss of neurons in the brain. A thorough understanding of its mechanism is a prerequisite for discovering effective therapeutic interventions. N6-methyladenosine (m6A) is the most prevalent post-transcriptional RNA modification that plays important roles in gene regulation and many other biological processes including neurodevelopment, learning and memory. m6A is particularly abundant in the brain and its dysregulation has been associated with neurological disorders. Yet, we still do not have a complete map of m6A in the brain of older individuals and the mechanism by which m6A dysregulation may causally contribute to AD also remains an enigma. We have recently developed several novel technologies for transcriptome-wide quantitative m6A profiling at base-resolution. We have also validated the methods in a pilot study consisting of 60 postmortem prefrontal cortex and identified multiple m6A alterations associated with cognitive phenotypes and AD neuropathology (e.g., amyloid-β, tau tangles). Using these novel technologies, the current study will test the hypothesis that brain m6A dysregulation is causally implicated in AD pathology. Our objectives here are to 1) create the first high-resolution reference map of brain m6A methylome (i.e., all m6A sites in brain) in the brain of older adults; 2) identify specific m6A alterations associated with AD and its clinical and pathological endophenotypes; and 3) elucidate the mechanism by which m6A dysregulation may causally contribute to AD pathogenesis. To achieve these goals, we leverage a large collection of human postmortem brain tissue samples (dorsolateral prefrontal cortex) in two community-based cohorts of aging and dementia: Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Deep clinicopathological phenotypes and rich brain omics data sets (e.g., GWAS, epigenomics, transcriptomics, proteomics) are available in both cohorts. In Aim 1, we will perform quantitative profiling of brain m6A methylome and identify specific m6A alterations associated with AD neuropathology. Aim 2 will integrate m6A data with other brain omics data, including genomics (GWAS), epigenomics (DNA methylation, histone acetylation, and miRNA), transcriptomics (RNA-seq) and proteomics, in the same brain cortex of same individuals, to decipher the mechanism by which altered m6A methylation may trigger AD pathology. In Aim 3, we will use a dCas13b-FTO fusion for m6A editing in human induced pluripotent stem cells (iPSC)-derived neurons to functionally validate the top-ranked genes and determine the causal role of m6A dysregulation in AD pathogenesis. Such results will provide novel mechanistic insight into the role of m6A dysregulation in AD pathology and inform the development of therapeutic interventions targeting m6A and its regulatory pathways for AD treatment.

• Brain and blood N-glycome profiling in Alzheimer's disease

  7R01AG085469-02

  NIA · FY 2025 · $756K

  Project Summary Alzheimer’s disease (AD) is a major form of dementia, affecting about 55 millions of people worldwide. Despite substantial efforts, we still do not understand its underlying mechanisms, and thus no reliable biomarker or effective treatment has yet been developed. Protein N-glycosylation, the enzymatic process of adding N- glycans (i.e., sugars) to proteins, is the most common post-translational modification that regulates the function of most proteins. Aberrant N-glycosylation has been observed in key AD-related proteins such as APP, tau, and β-site APP-cleaving enzyme-1 (BACE1). N-glycans are diverse structured biomolecules that play crucial roles in various biological processes including brain development and signal transduction. Altered composition and structure of N-glycans have been associated with AD and neuroinflammation. Thus, characterizing the N- glycome (complete repertoire of all N-glycans in a biological sample) will facilitate the discovery of novel biomarkers and shed light on the role of N-glycosylation in AD pathology. Our preliminary data show that baseline serum N-glycans predicts AD onset and cognitive decline over time, and altered brain N-glycans are associated with AD pathology. However, a comprehensive landscape of the peripheral and central N-glycome in relation to AD is still lacking, especially in large-scale human populations. The mechanisms through which aberrant N-glycome expression contributes to AD also remain an enigma. We hypothesize that dysregulated serum N-glycome precedes and predicts AD onset, and aberrant brain N-glycome is causally implicated in AD pathology. Our objectives are to understand the mechanisms through which aberrant N-glycosylation affects AD and identify circulating glycan-based markers for early prediction and risk stratification. To achieve these, we leverage the large collection of biospecimens (antemortem serum and paired postmortem brains) in two community-based prospective cohorts of aging and dementia (ROS and MAP). We will use the high-resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) to comprehensively profile the blood (serum) and brain N-glycome in relation to AD (Aims 1 and 2). The potential causal role of aberrant N-glycome expression in AD pathology will be examined by integrative multi-omics analyses, followed by functional validation in drosophila models of AD (Aim 3). In sum, this innovative project leverages the wealth of deep clinical and neuropathological phenotypes as well as multi-omics data (e.g., glycomics, genomics, epigenomics, and transcriptomics) in the same brain cortex, and provides unprecedented opportunities to uncover novel mechanisms underlying AD. Our proposal brings together an exceptionally strong and unique multi-disciplinary team with complementary expertise needed to achieve our goals. Findings of this study will significantly enhance our understanding of the mechanisms through which aberrant N-glycosylation contributes to AD, and are likely to lead to novel mechanistic markers for early prediction, risk stratification, and therapeutic targets towards precision treatment of AD.

• Sociocultural factors, DNA methylation and Risk of Diabetes in Hispanics/Latinos

  7R01DK137254-03

  NIDDK · FY 2025 · $655K

  Hispanics/Latinos, the largest and fastest-growing minority group in the US, are disproportionately affected by type 2 diabetes (T2D). Sociocultural, psychosocial, and behavioral factors [collectively called “socioenvironmental factors” hereafter] are believed to contribute to T2D disparity in Hispanics/Latinos, but the underlying biological mechanisms of action are unclear. DNA methylation (DNAm), one of the most studied epigenetic modifications, is responsive to various socioenvironmental exposures across an individual’s life course, and aberrant DNAm has been associated with aging and age-related diseases including T2D. To date, little is known about the genomewide DNAm patterns associated with socioenvironmental exposures [in totality named “socioenvironmental exposome”]. The mechanisms through which socioenvironmental exposome becomes biologically embedded into aging and risk of T2D have not been well studied in a nationally representative sample of Hispanics/Latinos. Building on our prior work, we hypothesize that altered DNAm evoked by socioenvironmental risk and protective factors contributes to risk for T2D in Hispanics/Latinos. Our objectives here are to characterize the socioenvironmental exposome in relation to risk of T2D, and identify key biological pathways through which socioenvironmental exposome affects risk of diabetes, independent of known risk factors. To achieve this, we leverage a wealth of deep clinical phenotypes and socioenvironmental factors collected by the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and its ancillary study - the Sociocultural Ancillary Study (SCAS). Using peripheral blood genomic DNA collected at baseline (2008-2011) from 3,323 non-diabetic Hispanics/Latinos (aged 18-74) followed through 2024, we will first identify unique latent constructs using a unified theoretical framework and then conduct epigenomewide association studies (EWAS) to identify methylated genes/regions in response to each unique socioenvironmental construct (Aim 1). Findings from Hispanics/Latinos will be replicated in non-Hispanic Whites, African Americans, and American Indians (total N=7,184). In Aim 2, we will prospectively determine whether socioenvironment-induced DNAm predict the onset and progression of T2D, independent of standard clinical factors. In Aim 3, we will perform integrated genetic and epigenetic analyses to identify causal epigenetic mediators and molecular pathways through which socioenvironmental exposome become biologically embedded into diabetes risk in Hispanics/Latinos. Successful completion of this project will identify modifiable genes and causal pathways through which socioenvironmental factors become biologically embedded in Hispanic cardiometabolic health. Such results may provide novel mechanistic insights into disease pathology, and are likely to lead to culturally tailored precision strategies for diabetes prevention and intervention.

• Brain lipids and Alzheimer's Disease

  7R01AG081375-03

  NIA · FY 2025 · $638K

  Project Summary Alzheimer’s dementia (AD) affects over 35 million people worldwide, and this number is expected to triple by 2050. As early as a century ago, Alois Alzheimer noted three significant neuropathological features in the brain of AD patients: senile plaques, neurofibrillary tangles, and lipid granule accumulation. While senile plaques and neurofibrillary tangles are now widely accepted as hallmarks of AD pathology, and thus have been extensively studied, the role of lipid accumulation in AD pathogenesis has been less studied. Lipidomics is a new omics technique that can identify and accurately quantify hundreds to thousands of lipids in biospecimens in large- scale population studies. Using this technology, many lipid species have been reported to be associated with cognitive phenotypes and AD neuropathologies (e.g., amyloid-beta, tau tangles). However, several key knowledge gaps exist in this field. First, previous studies have largely focused on blood, but the brain lipidomic profile is likely different from that of blood. To date, little is known about the global lipid composition and individual lipid species that trigger neuropathologies in human AD brains. Second, of the few existing lipidomic studies in human AD brains, sample size was mostly small and results were inconsistent. Importantly, the coverage of brain lipidome (i.e., collection of all lipid species in brain) in previous studies was low, and thus many disease-related lipids have not been investigated. To date, a full spectrum of brain lipidome in relation to AD pathology is lacking, especially in large-scale epidemiological studies. Finally, the potential causal role of lipid regulation in brain aging and AD neuropathology remains largely unknown and unexplored. To address these important questions, we leverage the large-collection of postmortem brain tissue samples, the deep clinical and neuropathological phenotypes, and the rich brain omics data (e.g., genomics, epigenomics, and transcriptomics) in two community-based longitudinal cohorts of aging and dementia – the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Specifically, we will conduct the first comprehensive lipidomic profiling in 1,450 frozen dorsolateral prefrontal cortex (DLPFC) using the Metabolon’s Complex Lipid Panel (CLP), a mass spectrometry based platform that can identify and accurately quantify the absolute concentrations of up to 1,100 individual lipid species and 14 lipid classes in large-scale epidemiological studies. Our goals here are to 1) generate the first comprehensive reference map of brain lipidome in relation to Alzheimer’s dementia-phenotypes (Aim 1); 2) identify individual brain lipid species associated with AD neuropathologies and cognitive phenotypes (Aims 1 and 2); and 3) elucidate the potential causal role of altered brain lipid regulation in AD pathology (Aim 3). Such results will shed light on the mechanisms through which lipid accumulation in the aging brain affects AD pathology, and provide evidence for targeting lipid metabolism in developing novel therapeutics for AD prevention and treatment.

Earlier awards

• Genome-wide mapping and integrative analysis of DNA 6mA methylome in human AD brainFY 2023 · $491K