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Hedgehog Signaling in the Progression of Myelodysplastic Syndromes

骨髓增生异常综合征进展中的 Hedgehog 信号转导

基本信息

批准号：
9900860
负责人：
Lukasz Pawel Gondek
金额：
$ 17.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2017-04-05 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900860
关键词：
Acceleration Acute leukemia Address Age Age-Years Animal Model Animals Apoptosis Automobile Driving Binding Cell Maintenance Cell Proliferation Cell Surface Receptors Cells Chronic Myeloproliferative Disorder Clinic Clinical Research Clonal Hematopoietic Stem Cell Data Development Diagnosis Disease Disease Progression Dysmyelopoietic Syndromes Elderly Embryonic Development Epigenetic Process Erinaceidae FLT3 gene Faculty Fellowship Frequencies Genetic Genetic study Goals Hematologic Neoplasms Hematological Disease Hematology Hematopoiesis Hematopoietic stem cells Homeostasis Human Hypercellular Bone Marrow Impairment Individual Inferior Integral Membrane Protein Investigation K-Series Research Career Programs Knock-out Laboratories Lead Lesion Ligands Lymphoid Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mentors Mentorship Molecular Multiple Myeloma Mus Myelogenous Oncogenic Oncology Outcome Output Pathway interactions Patient-Focused Outcomes Patients Play Process Publishing Recurrent disease Regulation Reporting Research Research Personnel Role Signal Pathway Stress Syndrome Testing Therapeutic Intervention Time Training Programs Transforming Growth Factor beta Transgenic Animals Transgenic Mice Translational Research Universities aggressive therapy blood formation bone marrow failure syndrome cancer stem cell career chromosome 5q loss clinically significant cytopenia effective therapy gain of function hematopoietic differentiation high risk improved outcome in vivo innovation insight instructor lenalidomide leukemia leukemic transformation leukemogenesis member mouse model neoplastic cell notch protein novel novel therapeutics outcome forecast overexpression patient subsets peripheral blood prevent programs self-renewal skills smoothened signaling pathway targeted treatment therapeutic target transcription factor translational research program tumor

项目摘要

Project Abstract This proposal describes a research plan and a training program to facilitate Dr. Gondek’s transition from a junior faculty member to an independent investigator. Dr. Gondek studied the genetics of Bone Marrow Failure Syndromes and in particular Myelodysplastic Syndromes (MDS) in the laboratory of Dr. Jaroslaw Maciejewski at Cleveland Clinic. As a hematology fellow in the laboratory of Dr. William Matsui at The Johns Hopkins University, Dr. Gondek studied the role of Hedgehog (Hh) signaling in the development and progression of hematologic malignancies. Dr. Matsui, Dr. Gondek’s primary mentor, is a world-renowned expert in the field and was the first to report the importance Hedgehog signaling in the regulation of cancer stem cells in multiple myeloma and pancreatic cancer. Upon completion of his clinical and research fellowship Dr. Gondek joined the faculty as an Instructor of Oncology to develop the research translational program in MDS. Support from the K08 Career Development Award will enable Dr. Gondek to gain additional skills, receive mentorship and protected time to advance his academic career. Dr. Gondek’s goal is to become an independent investigator in and leader in MDS translational research. In this application Dr. Gondek will study the role of a key regulator of Hedgehog signaling, Gli2, in normal hematopoiesis and progression of MDS. Hedgehog signaling seems to be a promising target in human malignancies and its inhibition has shown to be effective in certain tumors. To this end, the efforts to explain the role of Hh in normal and malignant hematopoiesis focused on upstream components of the pathway (e.g. Patched and Smoothened) but the results have been ambiguous. In this proposal Dr. Gondek will elucidate the function of the key Hh regulator Gli2 in normal and malignant hematopoiesis and define the role Gli2 as a selective and safe therapeutic target. Using transgenic animal models the proposed research will elucidate the role of Gli2 loss and gain-of- function in normal hematopoiesis and MDS progression. These goals will be achieved through the following aims: 1) Determine the role of Gli2 loss in (a) normal definitive hematopoiesis and (b) MDS progression using Nup98-HoxD13 mouse model, 2) Determine the requirements of Gli2 activator for (a) normal hematopoiesis and its role in (b) progression of MDS. Results of this research will further the understanding of Gli2 function in normal and malignant hematopoiesis. The investigators hypothesize that this project will provide novel insights into the processes that drive MDS progression and may lead to strategies focused on targeted Gli2 inhibition as a new treatment for high risk MDS and leukemia.

项目摘要