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Human Endogenous retroviruses as potential early markers for Alzheimer's disease

人类内源性逆转录病毒作为阿尔茨海默病的潜在早期标志物

基本信息

批准号：
10493715
负责人：
Farah Bakhshian Rahmatpanah
金额：
$ 34.67万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-03 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10493715
关键词：
Acetylation Administrative Supplement Affect African American population Age Aging Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Antigens Applications Grants Attenuated Autopsy Brain Brain Diseases Brain Injuries Brain region Clinical Code Computing Methodologies Dementia Detection Disease Disease Progression Drosophila genus Early Diagnosis Elderly Elements Endogenous Retroviruses Enzyme-Linked Immunosorbent Assay Epigenetic Process Functional disorder Genes Genetic Transcription Genome Genomics Global Change Health Hippocampus (Brain)Human Human Genome Immune System Diseases Immune response Immunologic Markers Impaired cognition Individual Inflammation Life Expectancy Malignant neoplasm of cervix uteri Malignant neoplasm of ovary Malignant neoplasm of prostate Manuscripts Memory Methods Molecular Target Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Outcome Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Blood Mononuclear Cell Phase Plasma Prefrontal Cortex Prostatic Neoplasms Proteins Psyche structure Race Regulation Reporting Retrotransposon Risk Role Senile Plaques Symptoms Tissues United States National Institutes of Health Western Blotting cohort computerized tools diagnostic tool early detection biomarkers extracellular gene function immune function immunoregulation inflammatory marker mammalian genome mental state mild cognitive impairment neuron loss neuropsychiatric disorder novel overexpression parent grant pre-clinical prostate cancer progression religious order study tau Proteins tau aggregation therapy design tool tumor microenvironment

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a neurodegenerative disorder that is marked by progressive damage and loss of neurons in the central nervous system. Current diagnosis of Alzheimer's disease relies largely on documenting mental decline, at which point Alzheimer's has already caused severe brain damage. There is an urgent need for novel methods to detect Alzheimer's before these devastating symptoms begin. Identifying pending cognitive impairment at an early stage can help design interventions that may reduce the risk of cognitive decline. Human Endogenous Retroviruses (ERVs) have integrated into mammalian genome over millions of years and comprise up to 5–8% of the human genome, as compared to 1-2% of protein coding sequences. Compared to the numerous studies describing proteins and their functions, very few studies have been performed on the impact of human ERVs on health and disease. Understanding how each ERV modulates both itself and its related genomic elements – functional proteins, disease-associated antigens, or genomic regulators – is crucial in determining the impact that ERVs can have on human health and diseases. ERVs have been reported to be transcriptionally active in the brains of AD patients. In addition, ERV activation is also associated with cognitive impairment in mice. In the parent grant, NIH/NCI R01CA226570 “Aggressive prostate cancer of African Americans is correlated with regulation of immunoregulatory genes in stroma”, we proposed that an epigenetic control of the antiviral immune response pathways via ERVs in prostate tumor microenvironment may contribute to differences in prostate cancer progression among patients of different racial groups. ERVs are highly repetitive and present in multiple copies throughout genome making it difficult to study them using existing computational tools. Most studies use PCR that can detect a few ERVs. We have developed a computational tool to study ERVs at the genome level, allowing detection of ERV changes at the global level. Applying this novel computational method, we have been able to correlate clinical outcomes with ERVs expression in prostate and cervical cancer. Here, we propose to extend these studies to AD and hypothesize that changes in ERV activation contribute to the inflammation and pathophysiology in AD. We will examine our hypothesis in two aims. First, we will investigate the global changes in ERV expression in peripheral blood mononuclear cells (PBMCs) from AD and mild cognitive impairment (MCI) patients, as well as healthy individuals (age matched). Second, we will determine the global changes in ERV expression in hippocampus tissue from all three cohorts (age matched). Identification of ERV changes may not only provide novel molecular target for strategies aimed at attenuating retroviral element sensing to treat dementia and neuropsychiatric disorders, but may also serve as potential early biomarkers for AD.

项目总结