Lineages and pathophysiology of clonal histiocytic disorders

克隆组织细胞疾病的谱系和病理生理学

基本信息

批准号：
9754257
负责人：
Frederic Geissmann
金额：
$ 74.7万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-16 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754257
关键词：
Adult Affect Alleles BRAF gene Birth Bone Marrow Brain Characteristics Chromatin Clinical Complication Development Diagnosis Diagnostic Disease Embryo Embryonic Development Environmental Risk Factor Eosinophilic Granuloma Erdheim-Chester Disease Erythro Functional disorder Gene Expression Profile Genetic Models Genetic Transcription Goals Hematopoietic stem cells Heterogeneity Histiocytosis Human Characteristics Kupffer Cells Laboratories Lesion Leukocytes Liver Liver Fibrosis Microglia Modeling Molecular Mus Mutation Myelogenous Myeloid Cells Neoplasms Nerve Degeneration Neurodegenerative Disorders Organogenesis Outcome Pathogenesis Pathologic Pathway interactions Patients Phenotype Pulmonary Fibrosis Refractory Role Somatic Mutation Syndrome Testing Time Tissues Work Yolk Sac base brain cell experimental study histiocyte improved in vivo in vivo Model inhibitor/antagonist interest macrophage monocyte mouse model new therapeutic target novel novel therapeutic intervention outcome forecast prevent progenitor prognostic residence stem

项目摘要

Project Summary This project aims to characterize at the molecular, cellular and organismal levels the pathophysiology of clonal histiocytic disorders, exemplified by Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD). These diseases display a considerable heterogeneity in terms of prognostic and clinical presentation, and are characterized by the occurrence of neurodegenerative syndromes and liver and lung fibrosis, the mechanisms of which are mysterious. Their pathophysiology is largely unknown. Two recent discoveries offer an opportunity to re-evaluate the pathophysiology and molecular underpinning of clonal histiocytic disorders, improve their diagnostic, prognostic, and offer new therapeutic strategies. First, the discovery of somatic mutations of the RAS-ERK pathway in >70% of cases of LCH and ECD by us and others has led to new therapeutic approaches based on the use of BRAF inhibitors and has renewed interests in efforts toward solving the pathophysiology of these diseases. Second, an important revision of our understanding of myeloid development stems from recent works from our laboratory and others which have revealed that the tissue- resident macrophages found in adult mice originate from early hematopoietic progenitors from the yolk sac independent of hematopoietic stem cells (HSCs) and persist within their tissue of residence in adults. Following on this work, we made the novel hypothesis that somatic BRAF mutations in yolk sac progenitors may causes histiocytoses and we have developed in vivo models that allow to test this hypothesis experimentally. Our preliminary results indicate that conditional expression of a BRAFV600E allele in yolk sac hematopoietic progenitors in vivo does results in the accumulation of BRAFV600E macrophage clones in various tissues, and is responsible in particular for a neurodegenerative syndrome in adult mice, that recapitulates for the first time one of the most intriguing and adverse phenotypic characteristics of the human histiocytic neoplasms. We will (Aim 1) will investigate the molecular and cellular mechanisms that underlie the development of brain neurodegenerative disease and identify molecular pathways that drive pathological histiocytes, (Aim 2) determine the pathological roles of BRAFV600E macrophages outside the brain in vivo and in particular in liver fibrosis, and (Aim 3) investigate the efficiency of BRAF inhibitor administration in the murine models. These experiments will provide a proof of concept that a mutations in yolk sac progenitors can cause an histiocytic disease in adults, help elucidate the pathophysiology and mechanism of histiocytoses and some of their most adverse complication such as the neurodegenerative syndrome, and reveal novel therapeutic targets to be used in conjunction with, or alternatively to, BRAF inhibitors.

项目摘要该项目旨在以分子，细胞和生物水平来表征克隆的病理生理学组织细胞疾病，以Langerhans细胞组织细胞增多症（LCH）和Erdheim-Chester疾病（ECD）为例。这些疾病在预后和临床表现方面表现出相当大的异质性，并且是以神经退行性综合征和肝脏和肺纤维化为特征其中是神秘的。他们的病理生理学在很大程度上未知。最近的两个发现提供了机会重新评估克隆组织疾病的病理生理学和分子基础，请改善其诊断，预后，并提供新的治疗策略。首先，发现了躯体突变的在我们和其他人的LCH和ECD病例中，Ras-ERK途径> 70％导致了新的治疗基于使用BRAF抑制剂的方法，并为解决该抑制剂而努力解决了努力这些疾病的病理生理。第二，我们对髓样的理解的重要修订发展源于我们的实验室和其他作品的最新作品，这些著作表明组织 - 成年小鼠中发现的居民巨噬细胞起源于蛋黄囊的早期造血祖细胞独立于造血干细胞（HSC），并持续在其成人居住组织中。在这项工作之后，我们提出了一个新的假设，即蛋黄囊祖细胞中的体细胞BRAF突变可能导致组织细胞剂，我们已经开发了体内模型，可以检验此假设实验。我们的初步结果表明，蛋黄囊中BRAFV600E等位基因的条件表达体内造血祖细胞确实会导致brafv600e巨噬细胞克隆在各种组织，特别是成年小鼠神经退行性综合征的负责，这概括了第一次是人类组织细胞的最有趣和最不利的表型特征之一肿瘤。我们（AIM 1）将研究大脑发展的基础的分子和细胞机制神经退行性疾病并鉴定驱动病理性组织细胞的分子途径（AIM 2）确定体内大脑外部巨噬细胞的病理作用，尤其是在肝脏中纤维化和（AIM 3）研究BRAF抑制剂在鼠模型中的效率。这些实验将提供一个概念证明，即蛋黄囊祖细胞中的突变会导致成年人的组织细胞疾病，有助于阐明组织细胞的病理生理和机制，其中一些它们最不良的并发症，例如神经退行性综合征，并揭示新的治疗性与BRAF抑制剂一起使用或与BRAF抑制剂一起使用的靶标。