Decoding innate immune signaling in normal and myelodysplastic hematopoiesis

解码正常和骨髓增生异常造血中的先天免疫信号

• 批准号: 10347307
• 负责人: Daniel Starczynowski
• 金额: $ 71.6万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-10 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347307
• 关键词: Acute leukemia; Basic Science; Biology; Blood Cells; Bone Marrow; Chronic; Collection; Complex; Development; Disease; Dysmyelopoietic Syndromes; Failure; Foundations; Genetic; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hereditary Disease; Heterogeneity; Immune; Immune signaling; Knowledge; Laboratories; Modality; Molecular; Pathogenesis; Patients; Process; Receptor Signaling; Research; Role; Syndrome; TRAF6 gene; Toll-Like Receptor Pathway; Toll-like receptors; innate immune pathways; innovation; mouse model; novel therapeutics; programs; stem cell function

Abstract Research in my laboratory has made critical findings related to the molecular, cellular, and genetic basis of Myelodysplastic Syndromes (MDS), a complex and poorly understood hematopoietic stem cell (HSC) failure syndrome. The complexity and heterogeneity of MDS, and the lack of mouse models, remain as major obstacles to understanding and effectively treating this disease. A major focus of my lab has been the intersection of immune biology and MDS. Namely, we have uncovered and characterized genetically-driven aberrant activation of the Toll- like receptor (TLR) (i.e., innate immune) pathway in MDS HSC, and now have evidence that TLR signaling is a major unifying driver of MDS pathogenesis. While dissecting the role of TLR signaling in MDS HSC, we identified a critical function of TLR signaling in normal HSC, a finding that has broader implications in chronic immune-related disorders and hematopoietic processes. As such, my research program has developed transformative and innovative approaches to investigate the intersection of TLR signaling, hematopoiesis, and MDS, which serve as the foundation for this proposal: (i) to dissect the genetic, molecular, and cellular underpinnings of MDS, with an emphasis on genetically-driven activation of TLR signaling (Research Focus 1); (ii) to evaluate the developmental requirement of the TLR signaling hub, TRAF6, in normal HSC function and MDS (Research Focus 2); and, (iii) to use the knowledge gained by our basic research to identify and develop novel therapeutic modalities for the treatment of MDS (Research Focus 3). The proposed research will impact our understanding of the initiation, progression, and treatment of MDS.

摘要 我的实验室的研究取得了与分子、细胞和 骨髓增生异常综合征(MDS)的遗传学基础--一种复杂且鲜为人知的疾病 造血干细胞衰竭综合征。MDS的复杂性和异构性，以及 缺乏小鼠模型，仍然是理解和有效治疗的主要障碍 这种病。我的实验室的一个主要关注点是免疫生物学和MDS的交叉。 也就是说，我们已经发现并表征了Toll基因驱动的异常激活- MDS HSC中的类受体(TLR)(即先天免疫)途径，现在有证据表明 TLR信号是MDS发病的主要统一驱动因素。在剖析TLR的作用时 在MDS HSC中，我们确定了TLR信号在正常HSC中的关键功能，这是一个发现 这对慢性免疫相关疾病和造血过程有更广泛的影响。 因此，我的研究项目开发了变革性和创新性的方法来 研究TLR信号、造血和MDS的交叉点，它们作为 这项提议的基础：(I)剖析人的遗传、分子和细胞基础 MDS，重点是TLR信号的遗传驱动激活(研究重点1)； (Ii)评估TLR信号中枢TRAF6在正常HSC中的发育需求 功能和MDS(研究重点2)；以及，(Iii)使用从我们的基础知识 寻找和开发治疗MDS的新治疗方式的研究 (研究重点3)。这项拟议的研究将影响我们对启动的理解， MDS的进展和治疗。

项目成果

GMP-ing to Spatial Conclusions about Emergency and Leukemic Myelopoiesis.

GMP 分析有关紧急情况和白血病骨髓生成的空间结论。

• DOI: 10.1016/j.stem.2017.04.005
• 发表时间: 2017
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Niederkorn,Madeline;Starczynowski,DanielT
• 通讯作者: Starczynowski,DanielT

Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS.

• DOI: 10.1084/jem.20201544
• 发表时间: 2021-07-05
• 期刊: The Journal of experimental medicine
• 作者: Trowbridge JJ;Starczynowski DT
• 通讯作者: Starczynowski DT

TNFAIP3 Plays a Role in Aging of the Hematopoietic System.

• DOI: 10.3389/fimmu.2020.536442
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Smith MA;Culver-Cochran AE;Adelman ER;Rhyasen GW;Ma A;Figueroa ME;Starczynowski DT
• 通讯作者: Starczynowski DT

The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia.

• DOI: 10.1038/s41375-021-01394-z
• 发表时间: 2022-03
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Niederkorn M;Ishikawa C;M Hueneman K;Bartram J;Stepanchick E;R Bennett J;E Culver-Cochran A;Bolanos LC;Uible E;Choi K;Wunderlich M;Perentesis JP;M Chlon T;Filippi MD;Starczynowski DT
• 通讯作者: Starczynowski DT

Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.

• DOI: 10.7554/elife.78136
• 发表时间: 2022-08-30
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Choudhary, Gaurav S.;Pellagatti, Andrea;Agianian, Bogos;Smith, Molly A.;Bhagat, Tushar D.;Gordon-Mitchell, Shanisha;Sahu, Srabani;Pandey, Sanjay;Shah, Nishi;Aluri, Srinivas;Aggarwal, Ritesh;Aminov, Sarah;Schwartz, Leya;Steeples, Violetta;Booher, Robert N.;Ramachandra, Murali;Samson, Maria;Carbajal, Milagros;Pradhan, Kith;Bowman, Teresa, V;Pillai, Manoj M.;Will, Britta;Wickrema, Amittha;Shastri, Aditi;Bradley, Robert K.;Martell, Robert E.;Steidl, Ulrich G.;Gavathiotis, Evripidis;Boultwood, Jacqueline;Starczynowski, Daniel T.;Verma, Amit
• 通讯作者: Verma, Amit