Human Platelet Defects in Transcription Factor RUNX1 Haplodeficiency

转录因子 RUNX1 单倍体缺陷中的人血小板缺陷

• 批准号: 10304868
• 负责人: Angara Koneti Rao
• 金额: $ 45.4万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304868
• 关键词: 12-HETE; Abnormal Platelet; Acute leukemia; Address; Affect; Affinity; Alpha Granule; Amino Acids; Aspirin; Award; Binding; Biology; Blood; Blood Cells; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Platelets; Cardiovascular Diseases; Cell physiology; Cells; Cellular biology; Cessation of life; Clot retraction; Coagulation Process; Collaborations; Complex; Cultured Cells; Cyclic AMP; Cyclic GMP; Cytoplasmic Granules; DNA Binding; Defect; Disease; Distal; Down-Regulation; Event; Expression Profiling; Factor XIII; Factor XIIIa; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Heart Diseases; Hela Cells; Hematopoiesis; Hemorrhage; Homeostasis; Human; Impairment; Individual; Inherited; Injury; Link; Megakaryocytes; Megakaryocytopoieses; Molecular; Molecular Biology; Mutation; Myeloid Cells; Myocardial Infarction; N-terminal; Patients; Phosphorylation; Plasma; Platelet aggregation; Play; Predisposition; Production; Protein Isoforms; Protein Kinase C; Proteins; RUNX1 gene; Regulation; Research; Role; Site; Symptoms; T-Lymphocyte; Thrombocytopenia; Thrombopoiesis; Transcript; Transglutaminases; Universities; Variant; cardiovascular disorder risk; cardiovascular disorder therapy; clinical practice; cohort; human model; in vivo; inhibitor; insight; interest; novel therapeutics; phosphoric diester hydrolase; promoter; response; stem cells; transcription factor

Summary We have a longstanding research interest into the molecular basis of inherited platelet dysfunction. Transcription factor RUNX1 is a master regulator of hematopoiesis, megakaryopoiesis and thrombopoiesis. The overall goal of this project is to obtain insights into the molecular basis of the platelet dysfunction associated with human RUNX1 mutations and into the genes regulated by it in platelets/megakaryocytes (MK) through studies in patients with RUNX1 haplodeficiency (RHD), characterized by familial thrombocytopenia, platelet dysfunction and a predisposition to acute leukemia. They have abnormalities in platelet granules and impaired platelet responses. Our platelet expression profiling of a RHD patient, one of the first platelet profiling studies in a patient with inherited platelet dysfunction, showed several genes are down regulated, some are direct RUNX1 targets, and affect specific aspects of platelet/MK biology. RHD is an important human model and untapped reservoir of information into platelet/ MK biology. Studies supported by the current R01 Award have been highly successful and extend the relevance of RUNX1 regulation of genes from bleeding disorder to CV disease. We propose studies on the RUNX1 regulation of 2 genes whose expression is decreased in RHD platelets: coagulation factor XIIIa (gene F13A) and phosphodiesterase E5A (PDE5A); little is known regarding their regulation. Aim 1 is to study the mechanisms and effects of decreased MK/platelet expression of F13A and PDE5A in RHD. F13A is synthesized by MK, (~3% of platelet protein) and regulates clot retraction. PDE5A regulates cGMP levels, a major regulator of platelet responses. We will perform studies in RHD patient platelets and in cultured cells, (HEL cells and MK generated from IPSCs from a RHD patient). We will assess association of RUNX1 regulation of these genes in vivo and in relation to future death and MI in patients with heart disease. RUNX1 is expressed from two alternate promoters – a distal P1 and a proximal P2 promoter, leading to two distinct proteins, RUNX1C and RUNX1B, with differential effects. Aim 2 is to study the differential regulation of MK/platelet genes by the RUNX1B and RUNX1C. Recent evidence suggests that RUNX1C is autoregulated by RUNX1. Aim 3 is to study the autoregulation of RUNX1 by RUNX1B and RUNX1C. Our studies will provide important, new information into the aberrant platelet/MK mechanisms in RHD, the differential gene regulation by RUNX1 variants and their downstream effects, and the relationship to CV disease. They will lay the basis for developing newer antithrombotic strategies.

总结

项目成果

Alterations in insulin-signaling and coagulation pathways in platelets during hyperglycemia-hyperinsulinemia in healthy non-diabetic subject.

• DOI: 10.1016/j.thromres.2014.06.029
• 发表时间: 2014-09
• 期刊: THROMBOSIS RESEARCH
• 影响因子: 7.5
• 作者: Rao, A. Koneti;Freishtat, Robert J.;Jalagadugula, Gauthami;Singh, Anamika;Mao, Guangfen;Wiles, Andrew;Cheung, Peter;Boden, Guenther
• 通讯作者: Boden, Guenther

Transcription Factor RUNX1 Regulates Platelet PCTP (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events: Differential Effects of RUNX1 Variants.

• DOI: 10.1161/circulationaha.116.023711
• 发表时间: 2017-09-05
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Mao G;Songdej N;Voora D;Goldfinger LE;Del Carpio-Cano FE;Myers RA;Rao AK
• 通讯作者: Rao AK

Platelet disorders: the next generation is in.

血小板疾病：下一代已到来。

• DOI: 10.1182/blood-2016-04-703215
• 发表时间: 2016
• 期刊: Blood
• 影响因子: 20.3
• 作者: Rao,AKoneti;Songdej,Natthapol
• 通讯作者: Songdej,Natthapol

Nuclear factor-κB regulates expression of platelet phospholipase C-β2 (PLCB2).

• DOI: 10.1160/th15-09-0749
• 发表时间: 2016-10-28
• 期刊: Thrombosis and haemostasis
• 影响因子: 6.7
• 作者: Mao G;Jin J;Kunapuli SP;Rao AK
• 通讯作者: Rao AK

Spotlight on FLI1, RUNX1, and platelet dysfunction.

• DOI: 10.1182/blood-2013-10-533166
• 发表时间: 2013-12
• 期刊: Blood
• 影响因子: 20.3
• 作者: A. Rao