ULK-mediated autophagy of α-globin in ß-thalassemia
α-地中海贫血中 ULK 介导的 α-珠蛋白自噬
基本信息
- 批准号:10539754
- 负责人:
- 金额:$ 65.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAdultAffectAllelesAnemiaApoptosisAttenuatedAutophagocytosisBiological MarkersBiologyCD34 geneCell LineCellsChronicComplexDataDeformityDiseaseDoseErythroblastsErythrocyte TransfusionErythrocytesErythroidErythroid CellsErythropoiesisFRAP1 geneFunctional disorderGene MutationGeneticGlobinGoalsHematological DiseaseHematopoietic Stem Cell TransplantationHematopoietic stem cellsHemoglobinHemoglobinopathiesHemolysisHumanImpairmentIn VitroIronIron ChelationIron OverloadLifeMediatingMessenger RNAMicroRNAsMusNewborn InfantOxygenPathologyPathway interactionsPatientsPharmacologyPhosphotransferasesPre-Clinical ModelProcessProductionProtein KinaseProteinsQuality ControlRegulationReportingRepressionSTK11 geneSeveritiesSickle Cell TraitSirolimusTestingThalassemiaTherapeuticTherapeutic EffectTranslatingTransplantationalpha Globinbasebeta Globinbeta Thalassemiabonecofactorcytotoxichepcidinimprovedin vivoinhibitorinnovationinsightlow and middle-income countriesmimeticsnew therapeutic targetnovel therapeuticspreventprotein aggregationprotein degradationproteostasisresponsetreatment strategy
项目摘要
PROJECT SUMMARY
Our long-term goal is to better define the proteostasis pathways that coordinate erythropoiesis, a specialized
process distinguished by massive hemoglobin synthesis and the elimination of most other proteins. This
application investigates how protein quality control modulates ß-thalassemia, a common hemoglobinopathy
caused by HBB gene mutations that impair the production of the ß-globin subunit of adult hemoglobin (HbA,
α2ß2). Consequently, free α-globin forms cytotoxic precipitates that cause maturation arrest and apoptosis of
erythroid precursors (ineffective erythropoiesis) and hemolysis, leading to anemia, bone deformities and iron
overload. Current therapies, including red blood cell transfusion, iron chelation and hematopoietic stem cell
transplantation for selected patients, are effective but not uniformly available, particularly in low/middle income
countries where the disease is most prevalent. Hence, new therapies are needed. Our preliminary data
demonstrate that the Unc-51–like autophagy activating kinase 1 (ULK1) mediates the autophagy of free α-globin
in ß-thalassemia. In general, ULK1 is inhibited by the mammalian target of rapamycin complex 1 (mTORC1)
kinase and stimulated by AMP-activated protein kinase (AMPK). Administration of the mTORC1 inhibitor
rapamycin to HbbTh3/+ mice, a validated preclinical model for ß-thalassemia, stimulated the autophagy of free α-
globin to reduce ineffective erythropoiesis and hemolysis in an ULK1-dependent fashion. Our data support the
central hypothesis that mTORC1 inhibition or AMPK activation can alleviate the pathophysiology of ß-
thalassemia by stimulating ULK1-mediated autophagic clearance of free α-globin. We will test this by: Aim 1,
optimizing the pharmacological inhibition of mTORC1 for ULK1 activation in HbbTh3/+ mice and by defining the
regulatory circuitry of α-globin autophagy in mouse and human ß-thalassemic erythroblasts; Aim 2, determining
whether elemental iron, a known activator of mTORC1, suppresses ULK1-mediated clearance of α-globin in ß-
thalassemic erythroblasts and whether this deleterious effect can be prevented by iron restriction; and Aim 3,
elucidating the genetic interactions between ß-thalassemia and miR-451, an abundantly expressed erythroid
microRNA that we showed to inhibit the LKB1 kinase and its substrate AMPK. In support of Aim 3, disruption of
the bi-cistronic miR-144/451 locus in HbbTh3/+ mice caused a reduction in α-globin precipitates and ß-thalassemia
pathologies. Overall, our studies promise to elucidate the biology of proteostasis networks that maintain balanced
hemoglobin synthesis through targeted protein degradation and validate mTORC1, AMPK and ULK1 as
“druggable” targets for novel ß-thalassemia therapies.
项目总结
我们的长期目标是更好地定义协调红细胞生成的蛋白平衡途径,这是一种专门的
以大量合成血红蛋白和消除大多数其他蛋白质为特征的过程。这
应用程序研究蛋白质质量控制如何调节一种常见的血红素病--地中海贫血
由HBB基因突变导致的,该突变损害成人血红蛋白(HBA,
α2?2)。因此,游离的α-珠蛋白形成细胞毒性沉淀物,导致成熟停滞和细胞凋亡
红系前体细胞(无效的红细胞生成)和溶血,导致贫血、骨骼畸形和铁
超载。目前的治疗方法包括红细胞输注、铁螯合和造血干细胞
对于选定的患者,移植是有效的,但并不是所有人都可以获得,特别是在中低收入者
这种疾病最流行的国家。因此,需要新的治疗方法。我们的初步数据
UNC-51样自噬激活蛋白1(ULK1)介导游离α珠蛋白的自噬
在贝氏-地中海贫血。一般来说,ULK1被雷帕霉素复合体1(MTORC1)的哺乳动物靶点抑制。
并受AMP激活的蛋白激酶(AMPK)刺激。MTORC1抑制剂的给药
雷帕霉素对HbbTh3/+小鼠的作用,一种经验证的贝型地中海贫血的临床前模型,刺激游离α-
珠蛋白以ULK1依赖的方式减少无效的红细胞生成和溶血。我们的数据支持
中心性假说:抑制mTORC1或激活AMPK可缓解?
通过刺激ULK1介导的自噬清除游离α-珠蛋白而导致的地中海贫血。我们将通过以下方式进行测试:目标1,
优化mTORC1对HbbTh3/+小鼠ULK1激活的药理抑制作用
小鼠和人的α-珠蛋白自噬调节回路;目的2,测定
已知的mTORc1激活剂-元素铁是否抑制ULK1介导的α-珠蛋白清除
地中海贫血红细胞以及这种有害影响是否可以通过限制铁来预防;以及目标3,
β-地中海贫血与高表达红系miR-451基因相互作用的研究
我们发现的microRNA对LKB1激酶及其底物AMPK有抑制作用。为支持目标3,中断
HbbTh3/+小鼠体内的双顺反子miR-144/451基因座导致α-珠蛋白沉淀物减少,并导致β-地中海贫血
病理学。总体而言,我们的研究有望阐明维持平衡的蛋白质平衡网络的生物学。
通过靶向蛋白降解合成血红蛋白并验证mTORC1、AMPK和ULK1作为
“可用药的”新的地贫疗法的靶点。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Mitchell J Weiss其他文献
Adenine Base Editing Improves Erythropoiesis in Diamond-Blackfan Anemia Syndrome Patient-Derived Induced Pluripotent Stem Cells
- DOI:
10.1182/blood-2024-209312 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Shruthi Suryaprakash;Lei Han;Garret Manquen;Varun Katta;Damian Krzyzanowski;Jayaram Prasad;Nikitha Nimmagada;Kalin Mayberry;Nana Liu;Yan Ju;Yu Yao;Kelsey Ray;Marcin Wlodarski;Shengdar Q Tsai;Jonathan S Yen;Mitchell J Weiss;Senthil Velan Bhoopalan - 通讯作者:
Senthil Velan Bhoopalan
Testing Rapamycin As an Anti-Adhesion Therapy for Sickle Cell Disease
- DOI:
10.1182/blood-2024-212384 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Danitza Nebor;Mitchell J Weiss;Jonathan M. Flanagan - 通讯作者:
Jonathan M. Flanagan
Hematopoietic Stem Cells Supporting Fetal Erythropoiesis Are Differentially Regulated By Small and Large Ribosomal Subunits
- DOI:
10.1182/blood-2024-210699 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Yuefeng Tang;Te Ling;Rashid Mehmood;Mushran Khan;Julien Papoin;James Palis;Laurie A. Steiner;Sébastien Durand;Leonard I. Zon;Senthil Velan Bhoopalan;Mitchell J Weiss;Jeffrey Michael Lipton;Naomi Taylor;Patrick G. Gallagher;Mohandas Narla;John D. Crispino;Lionel Blanc - 通讯作者:
Lionel Blanc
Identification of Breakpoints of emRHD/em Hybrid Alleles By Long-Read Sequencing
通过长读长测序鉴定 emRHD/em 杂合等位基因的断点
- DOI:
10.1182/blood-2024-198223 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:23.100
- 作者:
Ti-Cheng Chang;Jing Yu;Bensheng Ju;Melanie Loyd;Granger Ridout;Geoffrey A.M. Neale;Jane S Hankins;Mitchell J Weiss;Gorka Ochoa;Sunitha Vege;Stella T. Chou;John Easton;Yan Zheng - 通讯作者:
Yan Zheng
miRNA-144/451 Regulates Cell Surface TfR1 Expression in Normal and β-Thalassemic Erythroblasts
- DOI:
10.1182/blood-2024-210302 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Georgios E. Christakopoulos;Alfonso G. Fernandez;Yu Yao;Rahul Telange;Dudley W. Michael;Tomas Ganz;Elizabeta Nemeth;Mitchell J Weiss - 通讯作者:
Mitchell J Weiss
Mitchell J Weiss的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Mitchell J Weiss', 18)}}的其他基金
ULK-mediated autophagy of α-globin in ß-thalassemia
α-地中海贫血中 ULK 介导的 α-珠蛋白自噬
- 批准号:
10649565 - 财政年份:2022
- 资助金额:
$ 65.26万 - 项目类别:
Trim58 and the Ubiquitin Proteasome System in Erythro-megakaryopoiesis
Trim58 和红细胞巨核细胞生成中的泛素蛋白酶体系统
- 批准号:
9242002 - 财政年份:2014
- 资助金额:
$ 65.26万 - 项目类别:
Regulation of erythropoiesis by the miR-144/451 microRNA locus
miR-144/451 microRNA 位点对红细胞生成的调节
- 批准号:
8726379 - 财政年份:2014
- 资助金额:
$ 65.26万 - 项目类别:
Trim58 and the Ubiquitin Proteasome System in Erythro-megakaryopoiesis
Trim58 和红细胞巨核细胞生成中的泛素蛋白酶体系统
- 批准号:
9025774 - 财政年份:2014
- 资助金额:
$ 65.26万 - 项目类别:
Trim58 and the Ubiquitin Proteasome System in Erythro-megakaryopoiesis
Trim58 和红细胞巨核细胞生成中的泛素蛋白酶体系统
- 批准号:
8843634 - 财政年份:2014
- 资助金额:
$ 65.26万 - 项目类别:
Regulation of erythropoiesis by the miR-144/451 microRNA locus
miR-144/451 microRNA 位点对红细胞生成的调节
- 批准号:
8868445 - 财政年份:2014
- 资助金额:
$ 65.26万 - 项目类别:
Trim58 and the Ubiquitin Proteasome System in Erythro-megakaryopoiesis
Trim58 和红细胞巨核细胞生成中的泛素蛋白酶体系统
- 批准号:
8819535 - 财政年份:2014
- 资助金额:
$ 65.26万 - 项目类别:
Regulation of erythropoiesis by the miR-144/451 microRNA locus
miR-144/451 microRNA 位点对红细胞生成的调节
- 批准号:
8546340 - 财政年份:2012
- 资助金额:
$ 65.26万 - 项目类别:
相似海外基金
Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
- 批准号:
2867610 - 财政年份:2023
- 资助金额:
$ 65.26万 - 项目类别:
Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
- 批准号:
BB/W009633/1 - 财政年份:2022
- 资助金额:
$ 65.26万 - 项目类别:
Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2021
- 资助金额:
$ 65.26万 - 项目类别:
Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
- 批准号:
459043 - 财政年份:2021
- 资助金额:
$ 65.26万 - 项目类别:
Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2020
- 资助金额:
$ 65.26万 - 项目类别:
Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10561642 - 财政年份:2019
- 资助金额:
$ 65.26万 - 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
- 批准号:
532989-2019 - 财政年份:2019
- 资助金额:
$ 65.26万 - 项目类别:
Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
- 批准号:
2243045 - 财政年份:2019
- 资助金额:
$ 65.26万 - 项目类别:
Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
- 批准号:
10359032 - 财政年份:2019
- 资助金额:
$ 65.26万 - 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
- 批准号:
428988 - 财政年份:2019
- 资助金额:
$ 65.26万 - 项目类别:
Studentship Programs