课题基金 / 基金详情

Astrocyte innate immune mechanisms of post-viral cognitive dysfunction

Astrocyte innate immune mechanisms of post-viral cognitive dysfunction
病毒后认知功能障碍的星形胶质细胞先天免疫机制
批准号:
10115451
负责人:
Robyn S Klein
金额:
$39.38万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-12-01 至 2022-05-31

项目摘要

项目成果

Robyn S Klein的其他基金

相似基金

相关文献

中文摘要
翻译
摘要
英文摘要
ABSTRACT This proposal is focused on the pivotal role of astrocytes in molecular mechanisms underlying neurocognitive sequelae of flavivirus encephalitis. WNV is the leading cause of domestically acquired arboviral disease in the United States. In addition to the acute neuroinvasive syndromes and persistent motor deficits, patients that recover from WN neuroinvasive disease (WNND) experience significant long-term cognitive sequelae, including high rates of memory impairment and abnormalities in executive function. We recently established a novel murine model of recovery from intracranial infection with a mutant WNV (WNV-NS5-E218A), which leads to ongoing microglia activation with synapse elimination, decreased adult neurogenesis, and spatial learning defects that persist months after viral clearance These effects on synapses were also observed in patients who succumbed to WNND. While these data provide some molecular explanations for poor spatial learning in WNV-recovered subjects, the mechanisms underlying lack of recovery of the hippocampal circuit are unclear. We recently demonstrated that WNND is associated with T cell-derived interferon(IFN)γ, and microglial-derived complement promote elimination of hippocampal CA3 presynaptic terminals, with lack of recovery due to the generation of interleukin(IL)-1β-expressing activated astrocytes. Indeed, inactivation of IL-1R1 signaling in WNV-recovered animals promotes adult neurogenesis, synaptic repair, and prevents defects in spatial learning. These reactive astrocytes also express recently identified markers of neurotoxicity (H2.D1, Gbp2, psmb8), suggesting viral-induced effects on cognition might be perpetuated by the generation of astrocytes with a redirected cell fate. Indeed, increased expression of some of these genes (GFAP, Gpb2, psmb8) is observed in human cortical astrocytes treated with IFNβ, also highly expressed within the WNV-infected CNS. Prior research has suggested multiple cellular origins of reactive astrocytes with activated microglia being a potential key player in directing astrogliosis18,19. Similarly, the activation of the inflammasome complex within myeloid cells has been implicated in IL-1β production with IL-1 targeting multiple cell types including neural precursor cells20,21. We hypothesize that macrophage-derived IL-1 directs neuronal precursor cells toward an astrocyte fate during viral encephalitis. We further hypothesize that during recovery, activated microglia promote the differentiation of astrocytes towards neurotoxic phenotypes that inhibit hippocampal repair and recovery from neurocognitive deficits via effects of innate immune cytokines on neural precursor cells (NPC). Aim 1: Define the cellular targets of astrocyte-derived, anti-neurogenic cytokines in neurocognitive dysfunction during recovery from flavivirus encephalitis. Aim 2: Define innate immune mechanisms that direct and maintain astrogliosis during WNV infection and recovery. Aim 3: Define astrocyte-specific responses to IFNβ that impact neural correlates of spatial memory during recovery from WNND.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
2023 Neuroimmune Communication in Health and Disease Gordon Research Conference and Gordon Research Seminar
  • 批准号:
    10609280
  • 项目类别:
  • 资助金额:
    $1.6万
  • 财政年份:
    2022
  • 负责人:
    Robyn S Klein
  • 依托单位:
Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS
  • 批准号:
    10397683
  • 项目类别:
  • 资助金额:
    $118.13万
  • 财政年份:
    2021
  • 负责人:
    Robyn S Klein
  • 依托单位:
Research Program Award (R35 Clinical Trial Optional) - Dr. Robyn Klein NINDS
  • 批准号:
    10239672
  • 项目类别:
  • 资助金额:
    $86.88万
  • 财政年份:
    2021
  • 负责人:
    Robyn S Klein
  • 依托单位:
Innate immune mechanisms of virologic control and recovery from flavivirus encephalitis
  • 批准号:
    10247164
  • 项目类别:
  • 资助金额:
    $77.53万
  • 财政年份:
    2020
  • 负责人:
    Robyn S Klein
  • 依托单位:
海外基金