Development of thrombopoietin mimetic (TPOm) as a mitigator against Radiation-induced endovascular injuries

开发血小板生成素模拟物（TPOm）作为辐射引起的血管内损伤的缓解剂

• 批准号: 10159203
• 负责人: Sanchita P Ghosh
• 金额: $ 46.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159203
• 关键词: Acute; Agonist; Anemia; Animal Model; Animals; Binding; Biological Assay; Blood Platelets; Blood Vessels; Bone Marrow; C57BL/6 Mouse; CSF3 gene; CSPG4 gene; Canis familiaris; Cell Transplantation; Cells; Development; Differentiation Inducer; Dose; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Epithelial; Exposure to; Female; Functional disorder; Genetically Engineered Mouse; Growth Factor; Hematopoietic; Hematopoietic stem cells; Human; Image; Imaging Techniques; Inflammatory; Injury; Intestines; KDR gene; Kidney; Late Effects; Leukopenia; Liver; Lung; MPL gene; Magnetic Resonance; Marrow; Mediating; Megakaryocytes; Mesenchymal; MicroRNAs; Modeling; Modification; Morbidity - disease rate; Multiple Organ Failure; Mus; Natural regeneration; Organ; Peptides; Perfusion; Pericytes; Peripheral; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma; Play; Radiation; Radiation Injuries; Radiation Protection; Radiation Tolerance; Radiation Toxicity; Radiation exposure; Radio; Rattus; Recovery; Role; Serum Markers; Site; Stem Cell Factor; Therapeutic; Thrombocytopenia; Thrombopoietin; Tissues; Translations; Treatment Factor; Vascular Endothelium; Villus; Whole-Body Irradiation; Work; animal rule; base; bone cell; cell injury; circulating biomarkers; cytokine; early detection biomarkers; efficacy validation; endothelial stem cell; experimental study; hematopoietic stem cell quiescence; hematopoietic stem cell self-renewal; improved; insight; irradiation; lead candidate; male; microCT; microRNA biomarkers; mimetics; minimally invasive; mortality; nonhuman primate; novel; nutrition; paracrine; peripheral blood; radiation countermeasure; radiation mitigation; radiation mitigator; radiation-induced injury; receptor; response; restoration; single photon emission computed tomography; stem cell niche; stem cell proliferation; stem cells; targeted agent; tissue regeneration; tissue stem cells; vascular factor; vascular injury

Abstract Radiation-induced vascular injury (RIVI) is a critical component of the multi-organ failure (MOF) seen in acute radiation syndrome (ARS), following exposure to whole or partial body irradiation. The pathophysiology of ARS results from a combination of direct cytocidal effects of irradiation (IR) on tissue stem and progenitor cells (TSPC) and niche cells with varying radiosensitivity. While several growth and differentiation agents targeting TSPCs are being actively pursued as therapeutics to treat ARS, it is evident that rapid restoration of the sinusoidal endothelial cells (SEC) in the stem cell niche cells is critical for improving survival in ARS and in ameliorating the delayed effects of acute radiation exposure (DEARE). SECs provide a conduit for nutrition and secrete angiocrine growth factors that support the proliferation of perivascular niche cells, such as, mesenchymal cells and TSPCs. Studies have implicated the essential role of the vascular component in acute radiation injuries of the bone marrow (BM) and intestine, as well as, in late effects in lung, liver and kidneys. In the bone marrow, the peri-arteriolar NG2+Nestinbright pericytes support hematopoietic stem cell (HSC) quiescence, while the peri-sinusoidal LepR+Nestindim mesenchymal cells promote HSC proliferation. Following exposure to IR, there is regression of BM-SEC with destruction of peri-sinusoidal niche cells and HSCs. VEGFR2-mediated regeneration of the marrow SECs is necessary for BM regeneration in ARS. We are collaborating with Janssen Pharmaceuticals on the development of a novel radiation countermeasure, thrombopoietin (TPO) mimetic (TPOm, aka JNJ-26366821), which is a Phase II ready, fully synthetic, PEGylated TPO receptor, c-MPL agonist peptide that reduces mortality and morbidity associated with BM-ARS. TPOm is unique amongst radiomitigators because of two distinct pharmacodynamic effects: (1) Mitigation of radiation-induced thrombocytopenia, anemia, and leukopenia upon binding and activation of the c-Mpl receptor on megakaryocytes and HSC, and (2) protection and regeneration of vascular endothelium, particularly SEC. A single dose of TPOm, administered 24 h post-whole body irradiation (WBI) improved survival significantly in multiple animal models of ARS, including mouse, rat, dog and non-human primates (NHP). TPO has also been shown to promote mobilization of vascular endothelial progenitor cells to sites of vascular injury. We, therefore, hypothesize that in addition to treating radiation-induced thrombocytopenia, TPOm would promote regeneration of SEC in multiple tissue stem cell niches, including bone marrow and intestine, thereby, accelerating tissue regeneration after radiation exposure. The proposal entails a step-wise plan to determine the radiomitigating efficacy of TPOm in vascular injuries at peripheral and tissue level under specific aim 1 using acute radiation injury model. These studies will focus on peripheral vascular damage, endothelial injury of the hematopoietic and perivascular niche (H-ARS model), and vascular endothelial injury in the crypt and villi (GI-ARS model). We will also validate the efficacy of TPOm in mice, determine its dose modification factor and its effect of inflammatory cytokine profiles under specific aim 2. Finally, we will determine its effects against DEARE of the lungs and kidney, identify early biomarkers of endothelial injury at systemic and tissue level and develop imaging techniques to assess the injury using high contrast micro-CT scanner.

摘要

项目成果

Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821).

• DOI: 10.1038/s41598-022-07426-7
• 发表时间: 2022-03-03
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kumar VP;Holmes-Hampton GP;Biswas S;Stone S;Sharma NK;Hritzo B;Guilfoyle M;Eichenbaum G;Guha C;Ghosh SP
• 通讯作者: Ghosh SP