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
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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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
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{{ 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:
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:
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:
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:
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