Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection

HIV/SIV 感染中大麻素调节神经炎症的表观遗传机制

基本信息

项目摘要

ABSTRACT HIV associated neurological disorder (HAND), a major comorbidity affecting about 30-50% of patients receiving suppressive anti-retroviral therapy is characterized by difficulties with attention, concentration, decision making and memory, depression and slowed movements. Although chronic activation of brain microglia is proposed to drive HAND, the molecular mechanisms remain ill defined. Emerging evidence has shown that epigenetic mechanisms involving aberrant DNA methylation may significantly contribute to the pathogenesis of multiple sclerosis, Parkinson’s and Alzheimer’s disease. Nevertheless, the role of DNA methylation specifically in HIV induced monocyte/microglia activation remains unknown. The fact that epigenetic marks are heritable and passed on to several generations of daughter cells during mitosis might explain a potential mechanism causing monocyte/microglial activation that may in turn help maintain persistent neuroinflammation in cART treated patients. Our preliminary studies identified significant upregulation of proinflammatory interferon stimulated and chemokine genes in basal ganglia and marked alterations in DNA methylation of CpG islands in promoters of genes associated with inflammatory response, apoptosis, dsDNA damage response and oxidative stress in colonic epithelium of chronically SIV-infected macaques, respectively. More importantly, chronic cannabinoid treatment to ART naïve SIV-infected rhesus macaques prevented proinflammatory gene expression in brain and epigenetic alterations suggesting their immense therapeutic potential for attenuating neuroinflammation and reduced HAND related symptoms. In the proposed studies, we will for the first time investigate changes in DNA methylation associated with delta-9-tetrahydrocannabinol (THC), cannabidiol, JWH133 (CB2R agonist) induced suppression of monocyte/microglial activation through the course of SIV infection. Further, we will determine the effect of combination anti-retroviral treatment (cART) in conjunction with chronic cannabinoid treatments on epigenetic alterations, viral reservoir, inflammation and endogenous cannabinoid levels in the blood and cerebrospinal fluid. Finally, we will investigate the receptor mediated and molecular mechanisms by which THC blocks endoplasmic reticulum stress, a key event in the onset of neurodegenerative diseases. The proposed research is highly innovative and applies state of the art immunological and molecular approaches to fill a significant gap in our understanding of the epigenetic mechanisms associated with HAND. As cannabinoids have shown great promise for the treatment of neurological disorders, the proposed studies are necessary, as it will provide a fundamental understanding of the epigenetic and endocannabinoid mechanisms underlying their anti- inflammatory effects. Finally, the results will have important therapeutic implications for immune modulation in not only HIV but also other chronic neuroinflammatory diseases.
摘要

项目成果

期刊论文数量(0)
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Siddappa N Byrareddy其他文献

Identification and Biological Characterization of Unique B/C Recombinant Strains of HIV-1 In Southern States of India
  • DOI:
    10.1186/1742-4690-2-s1-p126
  • 发表时间:
    2005-12-08
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Siddappa N Byrareddy;PK Dash;A Mahadevan;Anita Desai;N Jayasuryan;P Satishchandra;V Ravi;SK Shankar;U Ranga
  • 通讯作者:
    U Ranga
Immunological insights into the re-emergence of human metapneumovirus
对人偏肺病毒再次出现的免疫学见解
  • DOI:
    10.1016/j.coi.2025.102562
  • 发表时间:
    2025-06-01
  • 期刊:
  • 影响因子:
    5.800
  • 作者:
    Arpan Acharya;Siddappa N Byrareddy
  • 通讯作者:
    Siddappa N Byrareddy

Siddappa N Byrareddy的其他文献

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{{ truncateString('Siddappa N Byrareddy', 18)}}的其他基金

Targeting CNS reservoirs with CAR/CXCR5 T cells for the long-term remission of HIV
使用 CAR/CXCR5 T 细胞靶向 CNS 储存库以长期缓解 HIV
  • 批准号:
    10475466
  • 财政年份:
    2022
  • 资助金额:
    $ 70.45万
  • 项目类别:
Targeting CNS reservoirs with CAR/CXCR5 T cells for the long-term remission of HIV
使用 CAR/CXCR5 T 细胞靶向 CNS 储存库以长期缓解 HIV
  • 批准号:
    10677645
  • 财政年份:
    2022
  • 资助金额:
    $ 70.45万
  • 项目类别:
Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection
HIV/SIV 感染中大麻素调节神经炎症的表观遗传机制
  • 批准号:
    10434910
  • 财政年份:
    2020
  • 资助金额:
    $ 70.45万
  • 项目类别:
Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection
HIV/SIV 感染中大麻素调节神经炎症的表观遗传机制
  • 批准号:
    10656263
  • 财政年份:
    2020
  • 资助金额:
    $ 70.45万
  • 项目类别:
Limiting HIV establishment and maintenace by preserving intestinal immunity
通过保护肠道免疫力来限制艾滋病毒的建立和维持
  • 批准号:
    9891944
  • 财政年份:
    2017
  • 资助金额:
    $ 70.45万
  • 项目类别:
Limiting HIV establishment and maintenace by preserving intestinal immunity
通过保护肠道免疫力来限制艾滋病毒的建立和维持
  • 批准号:
    9450468
  • 财政年份:
    2017
  • 资助金额:
    $ 70.45万
  • 项目类别:
Limiting HIV establishment and maintenace by preserving intestinal immunity
通过保护肠道免疫力来限制艾滋病毒的建立和维持
  • 批准号:
    9349159
  • 财政年份:
    2017
  • 资助金额:
    $ 70.45万
  • 项目类别:
Targeting gut-brain axis to eliminate CNS reservoirs
瞄准肠脑轴消除中枢神经系统储库
  • 批准号:
    9350887
  • 财政年份:
    2017
  • 资助金额:
    $ 70.45万
  • 项目类别:
Transmitted/Founder SHIV macaque model
传播/创始人SHIV猕猴模型
  • 批准号:
    9204007
  • 财政年份:
    2015
  • 资助金额:
    $ 70.45万
  • 项目类别:
Transmitted/Founder SHIV macaque model
传播/创始人SHIV猕猴模型
  • 批准号:
    8847165
  • 财政年份:
    2015
  • 资助金额:
    $ 70.45万
  • 项目类别:

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Efficacy of MAT2A inhibitor to gastric cancer relating to aberrant DNA methylation
MAT2A 抑制剂对与异常 DNA 甲基化相关的胃癌的疗效
  • 批准号:
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    2021
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  • 批准号:
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  • 财政年份:
    2019
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Aberrant DNA Methylation Underlying Prenatal Exposures and Increased Newborn and Childhood Adiposity
异常 DNA 甲基化是产前暴露和新生儿和儿童肥胖增加的基础
  • 批准号:
    10543751
  • 财政年份:
    2019
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Aberrant DNA Methylation Underlying Prenatal Exposures and Increased Newborn and Childhood Adiposity
异常 DNA 甲基化是产前暴露和新生儿和儿童肥胖增加的基础
  • 批准号:
    10078610
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Risk prediction and early detection of colorectal cancer by aberrant DNA methylation in bowel lavage fluid
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针对异常DNA甲基化的子宫内膜癌新诊断和治疗研究
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