Latexin function in the maintenance and regeneration of the hematopoietic system

乳胶素在造血系统的维持和再生中的作用

基本信息

批准号：
10298039
负责人：
Ying Liang
金额：
$ 38.17万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298039
关键词：
Acute Aging Amino Acids Angiotensin II Apoptosis BCL2 gene Binding Binding Proteins Blood Blood Cells Bone Marrow Bone Marrow Cells Bone Marrow Transplantation Cancer Patient Carboxypeptidase Carboxypeptidase A Cellular Stress Development Dose Elderly Fluorouracil Funding Genes Genetic Genetic Transcription Goals HMGB2 Protein HMGB2 gene Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Hemorrhage Homing Ice Immune In Vitro Infection Injury Intervention Knockout Mice Knowledge Lead Legal patent Life Lymphoid Maintenance Malignant - descriptor Malignant Neoplasms Measures Mediating Molecular Mus Myelogenous Myelosuppression NF-kappa B Natural regeneration Output PC3.1 antigen Pancytopenia Pathologic Pathway interactions Patients Pharmacologic Substance Pharmacy (field)Physiological Process Protein Subunits Quality of life Radiation Radiation Protection Radiation therapy Regenerative capacity Regulation Regulator Genes Rejuvenation Reporting Ribosomal Proteins Risk Role Signal Transduction Stress System Therapeutic Time Transplantation Up-Regulation Work base cancer therapy cell injury cell regeneration drug discovery effective therapy functional decline genetic regulatory protein genome integrity hematopoietic stem cell aging hematopoietic stem cell self-renewal in vivo inhibitor/antagonist irradiation knock-down novel novel therapeutics overexpression preconditioning preservation prevent radiation response self-renewal senescence stem cell survival stem cells

Acute Aging Amino Acids Angiotensin II Apoptosis BCL2 gene Binding Binding Proteins Blood Blood Cells Bone Marrow Bone Marrow Cells Bone Marrow Transplantation Cancer Patient Carboxypeptidase Carboxypeptidase A Cellular Stress Development Dose Elderly Fluorouracil Funding Genes Genetic Genetic Transcription Goals HMGB2 Protein HMGB2 gene Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Hemorrhage Homing Ice Immune In Vitro Infection Injury Intervention Knockout Mice Knowledge Lead Legal patent Life Lymphoid Maintenance Malignant - descriptor Malignant Neoplasms Measures Mediating Molecular Mus Myelogenous Myelosuppression NF-kappa B Natural regeneration Output PC3.1 antigen Pancytopenia Pathologic Pathway interactions Patients Pharmacologic Substance Pharmacy (field)Physiological Process Protein Subunits Quality of life Radiation Radiation Protection Radiation therapy Regenerative capacity Regulation Regulator Genes Rejuvenation Reporting Ribosomal Proteins Risk Role Signal Transduction Stress System Therapeutic Time Transplantation Up-Regulation Work base cancer therapy cell injury cell regeneration drug discovery effective therapy functional decline genetic regulatory protein genome integrity hematopoietic stem cell aging hematopoietic stem cell self-renewal in vivo inhibitor/antagonist irradiation knock-down novel novel therapeutics overexpression preconditioning preservation prevent radiation response self-renewal senescence stem cell survival stem cells

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项目摘要

ABSTRACT The hematopoietic system is very sensitive to a variety of stresses. Radiation therapy commonly results in not only acute hematopoietic suppression but also long-term bone marrow (BM) injury with increased risk of BM failure or malignancy. Accumulation of damages during aging process is another type of stress on HSCs. Enhancing HSC survival and maintaining their genomic integrity upon stress are crucial for preservation of HSC self-renewal function and for protection against stress-induced BM injury. However, the underlying molecular mechanisms are not well defined. No effective treatment has been developed to prevent or treat stress-induced HSC damages and related pathological consequences. The primary goal of this project is to identify novel pharmaceutical compounds and transcriptional mechanism that target a HSC stress regulatory protein, latexin (Lxn), and to uncover the mechanisms that Lxn suppression results in radiation protection and HSC rejuvenation. We have identified a novel Lxn inhibitor small compound and found that it significantly increases survival by protecting HSCs via a newly identified canonical mechanism of carboxypeptidase A inhibition upon radiation. Lxn deletion also mitigates aging-related functional decline of HSCs. We hypothesize that pharmaceutical and transcriptional suppression of Lxn protects HSCs and blood system from stress (radiation and aging)-induced functional decline via the upregulation of canonical CPA3 pathway. Aim 1 is to determine the molecular mechanisms by which Lxn inactivation protects against radiation-induced BM injury via up-regulation of canonical CPA3 pathway. Aim 2 is to identify the mechanism of action of Lxn lead inhibitor in radiation protection of hematopoietic system. Aim 3 is to define the role of Lxn suppression in rejuvenating old HSCs. Findings will advance our knowledge of novel mechanisms how Lxn regulates stress hematopoiesis. Results will provide a compelling starting point and lay grounds for the novel drug discovery by targeting Lxn, which will benefit patients subject to radiation treatment and old people with dysfunctional HSC and immune aging.

抽象的造血系统对各种应力非常敏感。放射治疗通常导致仅急性造血抑制，但长期骨髓（BM）损伤，BM风险增加失败或恶性肿瘤。衰老过程中损害的积累是HSC上的另一种压力。增强HSC存活并在压力下保持其基因组完整性对于保存HSC至关重要自我更新功能和防止压力引起的BM损伤。但是，基础分子机制不是很好的定义。尚未开发出有效的治疗方法来预防或治疗压力引起的 HSC损害和相关的病理后果。该项目的主要目标是确定小说靶向HSC应激调节蛋白乳胶蛋白的药物化合物和转录机制（LXN），并发现LXN抑制导致辐射保护和HSC恢复的机制。我们已经确定了一种新型的LXN抑制剂小化合物，发现它通过通过新鉴定的羧肽酶A抑制辐射的规范机制保护HSC。 LXN缺失还减轻HSC与衰老相关的功能下降。我们假设该药物和 LXN的转录抑制可保护HSC和血液系统免受压力（辐射和衰老）诱导的通过规范CPA3途径的上调功能下降。目标1是确定分子 LXN失活通过上调来防止辐射诱导的BM损伤的机制 CPA3途径。目标2是确定LXN铅抑制剂在辐射保护中的作用机理造血系统。目的3是定义LXN抑制在使旧HSC恢复活力中的作用。调查结果会促进我们对新型机制的了解，LXN如何调节应力造血。结果将提供通过靶向LXN，引人入胜的起点和底层为新的药物发现，这将使患者受益受辐射治疗以及功能失调的HSC和免疫老化的老年人。