Targeted Manipulation of Stem Cells for AIDS Therapy
干细胞的靶向操作用于艾滋病治疗
基本信息
- 批准号:7479315
- 负责人:
- 金额:$ 50.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-02-01 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS therapyAcquired Immunodeficiency SyndromeAddressAdultApoptosisAreaCDKN2A geneCell CycleCell ProliferationCell divisionCell physiologyCellsCyclin-Dependent Kinase InhibitorDepthGeneticGenetic ScreeningGenotypeGoalsGrantHematological DiseaseHematopoietic stem cellsHomeostasisManipulative TherapiesMediator of activation proteinMolecularMusOutcomeParticipantPhenotypeProcessPurposeRegulationRegulatory PathwayRoleStem cellsTherapeuticbasecomparativegenetic analysisin vivoresearch studyself renewing cellself-renewalsmall hairpin RNAsuccess
项目摘要
DESCRIPTION (provided by applicant): This proposal is focused on cell intrinsic regulation of adult hematopoietic stem cells (HSC). The ultimate goal is to define molecular mediators of stem cell proliferation and self-renewal to enable manipulation of these for therapies, specifically therapies for blood disorders such AIDS. The prior grant period emphasized cyclin dependent kinase inhibitors (cdki), determining their role in stem cell homeostasis and how they could be manipulated to alter stem cell function. They defined in detail distinctive phenotypes associated with the genetic deficiency of p21Cip1 (p21), p27Kip1 (p27), p18INK4c (p18) and p16INK4a (p16). The phenotypes were different for each genotype, specifically in the areas of stem cell cycling and its three potential outcomes: self-renewal, differentiation and programmed cell death. This proposal will complete and build on that information, examining the molecular basis for these processes using independent, complementary genetic strategies to define how stem cells accomplish a self-renewing cell division. They will address the following specific aims:
1. Use an unbiased forward genetic screen to identify molecular participants controlling HSC self-renewal and proliferation. These experiments exploit the limited ability to maintain HSC ex vivo to select for shRNA enable expansion of HSC as demonstrated by in vivo function.
2. Identify the molecular mediators of HSC self-renewal and proliferation by comparative genetic analysis of cdki deficient mice with distinctive phenotypes
3. Validate the candidate molecular mediators of self-renewal and proliferation using in vivo analyses.
Success of this project will provide both in depth understanding of key regulatory pathways for adult HSC and create targeted approaches to manipulate stem cell self-renewal for therapeutic purposes.
描述(由申请人提供):该提案集中于成体造血干细胞(HSC)的细胞内在调节。最终目标是确定干细胞增殖和自我更新的分子介质,以使这些治疗,特别是血液疾病如艾滋病的治疗。前一个资助期强调细胞周期蛋白依赖性激酶抑制剂(cdki),确定它们在干细胞稳态中的作用,以及如何操纵它们来改变干细胞功能。他们详细定义了与p21Cip1(p21)、p27Kip1(p27)、p18INK4c(p18)和p16INK4a(p16)遗传缺陷相关的独特表型。每个基因型的表型都不同,特别是在干细胞循环及其三个潜在结果方面:自我更新,分化和程序性细胞死亡。该提案将完成并建立在这些信息的基础上,使用独立的互补遗传策略来研究这些过程的分子基础,以确定干细胞如何完成自我更新的细胞分裂。它们将针对以下具体目标:
1.使用无偏倚的正向遗传筛选来鉴定控制HSC自我更新和增殖的分子参与者。这些实验利用了离体维持HSC的有限能力来选择shRNA,使得HSC能够扩增,如通过体内功能所证明的。
2.不同表型cdki基因缺陷小鼠比较遗传学分析鉴定HSC自我更新和增殖的分子介导因子
3.使用体内分析确定自我更新和增殖的候选分子介质。
该项目的成功将提供对成人HSC关键调控途径的深入理解,并创造有针对性的方法来操纵干细胞自我更新以达到治疗目的。
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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David T Scadden其他文献
The hematopoietic stem cell in its place
造血干细胞在它的位置上
- DOI:
10.1038/ni1331 - 发表时间:
2006-03-20 - 期刊:
- 影响因子:27.600
- 作者:
Gregor B Adams;David T Scadden - 通讯作者:
David T Scadden
Osteoclasts eat stem cells out of house and home
破骨细胞把干细胞赶尽杀绝。
- DOI:
10.1038/nm0606-610 - 发表时间:
2006-06-01 - 期刊:
- 影响因子:50.000
- 作者:
Louise E Purton;David T Scadden - 通讯作者:
David T Scadden
Cancer stem cells refined
癌症干细胞的提纯
- DOI:
10.1038/ni0704-701 - 发表时间:
2004-07-01 - 期刊:
- 影响因子:27.600
- 作者:
David T Scadden - 通讯作者:
David T Scadden
David T Scadden的其他文献
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{{ truncateString('David T Scadden', 18)}}的其他基金
Functional consequences of stem and progenitor cell heterogeneity
干细胞和祖细胞异质性的功能后果
- 批准号:
10413502 - 财政年份:2020
- 资助金额:
$ 50.08万 - 项目类别:
Enhancing regeneration of stem cell-derived HIV-specific immune effectors
增强干细胞衍生的 HIV 特异性免疫效应器的再生
- 批准号:
10163909 - 财政年份:2020
- 资助金额:
$ 50.08万 - 项目类别:
Enhancing regeneration of stem cell-derived HIV-specific immune effectors
增强干细胞衍生的 HIV 特异性免疫效应器的再生
- 批准号:
10409803 - 财政年份:2020
- 资助金额:
$ 50.08万 - 项目类别:
Functional consequences of stem and progenitor cell heterogeneity
干细胞和祖细胞异质性的功能后果
- 批准号:
10188996 - 财政年份:2020
- 资助金额:
$ 50.08万 - 项目类别:
Clonal tracking and molecular characterization of hematopoiesis under stress
应激条件下造血的克隆追踪和分子特征
- 批准号:
10413504 - 财政年份:2020
- 资助金额:
$ 50.08万 - 项目类别:
Enhancing regeneration of stem cell-derived HIV-specific immune effectors
增强干细胞衍生的 HIV 特异性免疫效应器的再生
- 批准号:
10601073 - 财政年份:2020
- 资助金额:
$ 50.08万 - 项目类别:
Project 1: Implications of blood cell heterogeneity for CV disease
项目 1:血细胞异质性对心血管疾病的影响
- 批准号:
10238040 - 财政年份:2019
- 资助金额:
$ 50.08万 - 项目类别:
Project 1: Implications of blood cell heterogeneity for CV disease
项目 1:血细胞异质性对心血管疾病的影响
- 批准号:
10469350 - 财政年份:2019
- 资助金额:
$ 50.08万 - 项目类别:
Project 1: Implications of blood cell heterogeneity for CV disease
项目 1:血细胞异质性对心血管疾病的影响
- 批准号:
10670732 - 财政年份:2019
- 资助金额:
$ 50.08万 - 项目类别:
Functional consequences of stem and progenitor cell heterogeneity
干细胞和祖细胞异质性的功能后果
- 批准号:
10641537 - 财政年份:2017
- 资助金额:
$ 50.08万 - 项目类别:
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