Modeling intestinal dysfunction in HIV infection with organoid technology

利用类器官技术模拟 HIV 感染的肠道功能障碍

基本信息

  • 批准号:
    10542390
  • 负责人:
  • 金额:
    $ 78.98万
  • 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
  • 起止时间:
    2020-01-10 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Disruption of intestinal epithelial barrier function is an important cause of HIV-associated chronic immune activation but underlying molecular mechanisms are not known. The central hypothesis of this proposal is that HIV infection impairs the regenerative capacity of intestinal stem cells, resulting in long-lasting barrier dysfunction. This hypothesis was formulated on the basis of available data in the literature showing that in inflammatory bowel diseases, the intestinal stem cell pool and the compositional balance of intestinal cell types is disrupted, and our own published results showing intestinal stem cell proliferation is impaired in a subgroup of HIV+ patients with high systemic inflammation and poor clinical outcome. Intestinal stem cell function can be tested in vitro by expanding them into self-organizing three-dimensional structures termed “organoids”. They can be further differentiated into all intestinal epithelial cell types. This proposal leverages access to intestinal stem cells through intestinal biopsies by Dr. Ma Somsouk, an expert in HIV-associated gut inflammation, and expertise in organoid growth and basic HIV virology present in Dr. Melanie Ott's laboratory to examine intestinal stem cell function and organoid growth in HIV infection. The central hypothesis will be tested in two specific aims: 1) To define how HIV infection influences intestinal stem cell function in T cell: organoid co-culture experiments. The working hypothesis is that early contact between intestinal stem cells and HIV-infected T cells leads to stem cell damage, impaired gut epithelial regeneration and long-lasting barrier dysfunction. This hypothesis will be tested in T cell: organoid co-culture models established in the Ott lab. We will determine the effect of HIV-infected T cells on organoid growth, differentiation, barrier function and transcription at the single-cell level. Candidate factors such as TNF-α or factors emerging from our studies will be added directly to organoid culture media to analyze effects on growth and differentiation. 2) To determine the effects of chronic HIV infection on intestinal stem cell function. Our working hypothesis is that intestinal stem cell function is altered in HIV+ individuals, especially those with late onset of treatment and poor immunological recovery. This hypothesis will be tested by comparing growth and differentiation of organoids grown from HIV-infected individuals with different onset of treatment or uninfected individuals using morphological, functional and single-cell RNA sequencing analysis. This proposal will provide detailed insight into fundamental processes within the gastrointestinal tract that impact infection, persistence, and comorbidities in people living with HIV and is as such well aligned with this RFA. It is innovative because it shifts the focus to intestinal stem cells and their ability to renew the gut epithelium for proper barrier functions. It also uses innovative new organoid technology combined with clinical studies aimed at explaining why barrier defects persist in patients despite ART. Thus, important advances in the basic biology and novel therapeutic approaches towards HIV- associated chronic immune activation are expected.
ABSTRACT Disruption of intestinal epithelial barrier function is an important cause of HIV-associated chronic immune activation but underlying molecular mechanisms are not known. The central hypothesis of this proposal is that HIV infection impairs the regenerative capacity of intestinal stem cells, resulting in long-lasting barrier dysfunction. This hypothesis was formulated on the basis of available data in the literature showing that in inflammatory bowel diseases, the intestinal stem cell pool and the compositional balance of intestinal cell types is disrupted, and our own published results showing intestinal stem cell proliferation is impaired in a subgroup of HIV+ patients with high systemic inflammation and poor clinical outcome. Intestinal stem cell function can be tested in vitro by expanding them into self-organizing three-dimensional structures termed “organoids”. They can be further differentiated into all intestinal epithelial cell types. This proposal leverages access to intestinal stem cells through intestinal biopsies by Dr. Ma Somsouk, an expert in HIV-associated gut inflammation, and expertise in organoid growth and basic HIV virology present in Dr. Melanie Ott's laboratory to examine intestinal stem cell function and organoid growth in HIV infection. The central hypothesis will be tested in two specific aims: 1) To define how HIV infection influences intestinal stem cell function in T cell: organoid co-culture experiments. The working hypothesis is that early contact between intestinal stem cells and HIV-infected T cells leads to stem cell damage, impaired gut epithelial regeneration and long-lasting barrier dysfunction. This hypothesis will be tested in T cell: organoid co-culture models established in the Ott lab. We will determine the effect of HIV-infected T cells on organoid growth, differentiation, barrier function and transcription at the single-cell level. Candidate factors such as TNF-α or factors emerging from our studies will be added directly to organoid culture media to analyze effects on growth and differentiation. 2) To determine the effects of chronic HIV infection on intestinal stem cell function. Our working hypothesis is that intestinal stem cell function is altered in HIV+ individuals, especially those with late onset of treatment and poor immunological recovery. This hypothesis will be tested by comparing growth and differentiation of organoids grown from HIV-infected individuals with different onset of treatment or uninfected individuals using morphological, functional and single-cell RNA sequencing analysis. This proposal will provide detailed insight into fundamental processes within the gastrointestinal tract that impact infection, persistence, and comorbidities in people living with HIV and is as such well aligned with this RFA. It is innovative because it shifts the focus to intestinal stem cells and their ability to renew the gut epithelium for proper barrier functions. It also uses innovative new organoid technology combined with clinical studies aimed at explaining why barrier defects persist in patients despite ART. Thus, important advances in the basic biology and novel therapeutic approaches towards HIV- associated chronic immune activation are expected.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Melanie Maria Ott其他文献

Melanie Maria Ott的其他文献

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{{ truncateString('Melanie Maria Ott', 18)}}的其他基金

In vitro virology core
体外病毒学核心
  • 批准号:
    10512624
  • 财政年份:
    2022
  • 资助金额:
    $ 78.98万
  • 项目类别:
Modeling intestinal dysfunction in HIV infection with organoid technology
利用类器官技术模拟 HIV 感染的肠道功能障碍
  • 批准号:
    9894660
  • 财政年份:
    2020
  • 资助金额:
    $ 78.98万
  • 项目类别:
Modeling intestinal dysfunction in HIV infection with organoid technology
利用类器官技术模拟 HIV 感染的肠道功能障碍
  • 批准号:
    10083740
  • 财政年份:
    2020
  • 资助金额:
    $ 78.98万
  • 项目类别:
Modeling intestinal dysfunction in HIV infection with organoid technology
利用类器官技术模拟 HIV 感染的肠道功能障碍
  • 批准号:
    10322720
  • 财政年份:
    2020
  • 资助金额:
    $ 78.98万
  • 项目类别:
Single-Cell Transcriptomics of Non-Activated Latently Infected T cells Isolated from HIV+ Drug Users
从 HIV 吸毒者中分离出的非激活潜伏感染 T 细胞的单细胞转录组学
  • 批准号:
    10548752
  • 财政年份:
    2019
  • 资助金额:
    $ 78.98万
  • 项目类别:
Exploring HIV-associated Neurocognitive Disorder (HAND) and HIV Latency at the Single Cell Level in Cerebral Organoids
在脑类器官的单细胞水平上探索 HIV 相关神经认知障碍 (HAND) 和 HIV 潜伏期
  • 批准号:
    10466829
  • 财政年份:
    2019
  • 资助金额:
    $ 78.98万
  • 项目类别:
Harnessing the RNA-Binding Properties of Cas13a for HIV-1 Self-Testing
利用 Cas13a 的 RNA 结合特性进行 HIV-1 自检
  • 批准号:
    10423661
  • 财政年份:
    2019
  • 资助金额:
    $ 78.98万
  • 项目类别:
Harnessing the RNA-Binding Properties of Cas13a for HIV-1 Self-Testing
利用 Cas13a 的 RNA 结合特性进行 HIV-1 自检
  • 批准号:
    10456229
  • 财政年份:
    2019
  • 资助金额:
    $ 78.98万
  • 项目类别:
Exploring HIV-associated Neurocognitive Disorder (HAND) and HIV Latency at the Single Cell Level in Cerebral Organoids
在脑类器官的单细胞水平上探索 HIV 相关神经认知障碍 (HAND) 和 HIV 潜伏期
  • 批准号:
    10678898
  • 财政年份:
    2019
  • 资助金额:
    $ 78.98万
  • 项目类别:
PROJECT 2: Determine clinically relevant host-viral dependency networks for respiratory infections including SARS-CoV-2
项目 2:确定呼吸道感染(包括 SARS-CoV-2)的临床相关宿主病毒依赖性网络
  • 批准号:
    10550002
  • 财政年份:
    2018
  • 资助金额:
    $ 78.98万
  • 项目类别:

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