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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：
9367862
负责人：
Frederic Geissmann
金额：
$ 71.52万
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/9367862
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.

项目总结