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COBRE Phase II
The COBRE Center for Stem Cells and Aging grant has four projects dealing with stem cells and various aspects of aging, fibrosis and cellular senescence. The projects focus on hematopoietic stem cells, their microenvironment and the impact of aging on the fibrotic component of that microenvironment, neural stem cells, and their regulation with aging.
The renewal of our grant allows Lifespan and Rhode Island Hospital to update research infrastructure for expanded studies into normal and malignant stem cells. In turn, these upgrades in infrastructure will enhance Lifespan’s focus on establishing a comprehensive cancer and stem cell program that will foster the development of novel treatment strategies, conduct nationally recognized research efforts, and devise effective methods of cancer prevention
Promising applications for our research include regeneration and repair for the treatment of leukemia, lymphomas, various neurodegenerative disorders, and different aspects of aging.
Specific Aims of COBRE Phase II
COBRE Phase II aims to:
- Continue to provide an intellectual and financial foundation supporting our developing investigators with goals of academic development, R01 funding and independence. We support educational seminars, grant workshops and involvement of our grantees in national and international meetings.
- Encourage internal and external collaborative granting efforts by our investigators with ultimate goals of developing program project grants centered on our areas of interest such as aging, hematopoietic and neural stem cells and pulmonary hypertension.
- Develop a thematic multidisciplinary center, with a focus on stem cells and aging.
- Continue our successful recruitment of new junior investigators, who would also be candidates for COBRE support, to our research program.
- Support career development of our COBRE grantees with directed mentoring for achievement of specific project and individual milestones.
- Continue to work with local, state and federal leaders to contribute to the economic health of our state by providing sustainable careers in the medical sciences and significant amounts of extramural funding.
Project 1: Interrogating the Role of Abelson Interactor 1 in Age-Related Myelofibrosis
Molecular mechanisms that contribute to the pathology of myeloproliferative neoplasms at the stem cell level are not well understood. JAK/STAT cascade was found to be dysregulated in all types of myeloproliferative neoplasms – essential thrombocythemia, polycythemia vera and primary myelofibrosis. However, the extent to which currently available inhibitors that target JAK/STAT pathway alter the underlying disease and affect malignant hematopoietic stem cells is not clear.
Dr. Dubielecka’s long-term goal is to better understand the molecular processes responsible for malignant transformation of hematopoietic stem cells, and identify new targets for pharmacological intervention in myeloproliferative neoplasms.
The overall objective of this application is to identify new signaling mechanisms involved in the initiation of age-induced myelofibrosis and related myeloproliferative neoplasms. Her recent findings indicate that (1) conditional deletion of the gene encoding the Abelson interactor-1 (Abi-1) adapter protein in mouse bone marrow induces myelofibrotic phenotype, (2) hematopoietic progenitors and granulocytes from patients with primary myelofibrosis show decreased Abi-1 protein and transcript levels, (3) loss of Abi-1 positively affects activity of Src Family Kinases (SFKs) and their downstream signaling to STAT3 and NFkB, and finally (4) loss of Abi-1 in malignant hematopoietic stem cells leads to dysregulation of adhesion and quiescence and induces their chemo resistance.
The central hypothesis is that loss of Abi-1, through a positive effect on SFKs signaling and its downstream cross-talk with STAT3 and NF-kB, is a factor that initiates fibrosis-inducing changes at the malignant stem cell level.
Specific Aims of the Project
- The established Abi-1 conditional bone marrow-specific mouse model (Abi-1 BM KO) will be used to assess the effect of Abi-1 loss on the communication between hematopoietic stem cells and their microenvironment and its role in the development of age-related myelofibrosis.
- Advanced microscopy and biochemical arrays will be used to elucidate the mechanism by which Abi-1 directly controls SFKs and their downstream signaling to STAT3 and NFκB.
- Using Abi-1 BM KO, Dr. Dubielecka will evaluate the effects of SFKs inhibition on Abi-1-loss-induced myelofibrosis. Completion of these aims will elucidate Abi-1-driven mechanisms that lead to the development of marrow fibrosis induced by malignant stem cells in myeloproliferative neoplasms, and uncover potential new therapeutic approaches that directly address their pathogenesis. Our strategy utilizes newly established animal models and has the potential to significantly advance the understanding of tumor and stromal cell interactions. This knowledge will contribute to an emerging conceptual shift in the field from a focus on cancer cells to a broader and more complex understanding of cancer as a systemic disease existing in a microenvironmental context.
Project 2: Hematopoietic Bone Marrow Microenvironment in Aging and Age-related Leukemia
Dr. Liang is studying the role of the aged bone marrow microenvironment in normal hematopoiesis, the critical cell types for the hematopoietic niche and the role of SHIP inhibition in vivo in reconstitution of the aged and preleukemic microenvironments.
The increasing number of elderly people affected by age-related blood malignancies, mainly of the myeloid subtype, is one of the most significant public health challenges today but currently there are no effective treatments. The overall objective of this project is to investigate the role of bone marrow microenvironment in hematopoiesis and age-related leukemia. The COBRE Center for Stem Cells and Aging previously discovered that deficiency of the lipid phosphatase SHIP enables long-term reconstitution of the hematopoietic bone marrow microenvironment. This proposed study is a continuation of our prior work.
Specific Aims of the Project
- Investigate the role of aged bone marrow microenvironment in normal hematopoiesis.
- Identify and functionally evaluate critical cell types for the hematopoietic niche (Aim 2), and reconstitute aged and pre-leukemic bone marrow microenvironment via SHIP inhibition in vivo.
- The long-term goal of this project is to develop novel strategies for treatment of deadly blood diseases such as myelodysplastic syndromes, myeloproliferative neoplasms, myelofibrosis and acute myeloid leukemia in elderly people.
Project 3: Retrotransposable Element Expression in Neural Stem Cell Senescence and Aging
Dr. Kreiling’s research investigates the triggers for cellular senescence in neural stem cells, the resulting changes in chromatin structure leading to activation of retrotransposable elements and the consequences of these processes on cellular physiology.
Neurodegenerative conditions and dementias, including Alzheimer’s disease, create a significant economic burden and are responsible for considerable human suffering. Aging is the primary risk factor for development of these conditions. The decline in neural stem cell (NSC) function that occurs with age is a major factor contributing to the development of these conditions. However, the mechanisms resulting in NSC functional decline are poorly understood.
Recent work from Dr. Kreiling’s laboratory, and those of others’, reveals that chromatin undergoes global remodeling with age, with an opening of heterochromatic regions and a relative closing of euchromatic regions. The highly heterochromatic regions contain large numbers of retrotransposable elements (RTEs). RTE expression also increases with age and culminates in active transposition events. Somatic transposition can lead to insertional mutagenesis and genome rearrangements creating genome instability and triggering cellular senescence.
This leads to the hypothesis: Age-associated changes in chromatin structure lead to de-repression of RTEs, resulting in DNA damage and genome instability, ultimately triggering cellular senescence and a decline in NSC function.
To test this hypothesis, Dr. Kreiling’s lab will perform a set of experiments designed to determine the role of increased RTE expression with age in loss of NSC function.
Specific Aims of the Project
- Dr. Kreiling’s lab will begin by investigating the chromatin architecture in senescent and aged NSCs, and determine the effects on the transcriptome, specifically on the expression of RTEs. To obtain reinforcing and complementary whole genome data, she will use high-throughput Illumina sequencing in conjunction with three methods to define changes in chromatin structure and function: assay for transposase accessible chromatin (ATAC-seq), chromatin immunoprecipitation using antibodies against repressive and activating chromatin histone marks (ChIP-seq), and RNA-seq to define the transcriptome, including RTE expression.
- She will investigate the relationship between RTE expression and DNA damage accumulation in NSC functional decline. She will determine the dynamics of DNA damage accumulation and senescence in NSCs over time. The effects of RTE deregulation on NSC function and senescence will be determined using a reporter construct designed to over express the long interspersed nuclear element L1.
- Finally, Dr. Kreiling will determine the role of RTE expression in NSC functional decline in vivo. The effect of RTE de-repression on the ability of NSCs to regenerate neurons in the olfactory bulb will be investigated through olfactory discrimination tests in young and aged mice exposed to the reverse transcriptase inhibitor 3TC, which represses RTE transposition. To determine if RTE repression extends NSC health span, the neurogenic capabilities of NSCs will be investigated in 3TC treated mice. Taken together the results of the experiments outlined in this proposal will give new insight into the mechanisms that result in NSC functional decline with age and may ultimately lead to therapeutic interventions that can extend human health span.
Project 4: Regulation of Neural Stem Cell Quiescence by FOXO3 During Aging
The overarching goal of research in the Webb laboratory is to understand the molecular mechanisms responsible for aging and how stem cells are transformed to tumorigenic cancer stem cells. There are currently three areas of focus in the laboratory. First, the use of mouse models and genomics approaches to study the molecular mechanisms that regulate stem cell function in the mammalian brain. Second, investigation of strategies to target stem populations that cause brain cancer, called glioma stem cells. Third, a genomics approach to investigate the extent to which the mechanisms discovered in rodents are responsible for aging in humans.
Formation of new neurons from neural stem cells (NSCs) in the brain declines with age, but the mechanisms responsible remain unknown. Dr. Webb’s previous work has implicated the longevity-associated transcription factor FOXO3 as a key regulator of neural stem cell homeostasis in the adult brain. The goal of this study is to uncover the underlying mechanisms primarily through FACS-based approaches.
Specific Aims of the Project
- Determine the mechanisms underlying FOXO3-mediated NSC quiescence using in vitro models.
- Use in vitro models and FACS-based analysis to determine how changes in the FOXO3 network underlie the decline in NSC function with age.
- Determine the extent to which preservation of stem cells in vivo during aging affects cognitive function.
The overall outcome of this project will be the elucidation of the changes in NSCs that occur with age, and the mechanisms responsible for the loss of NSCs in aging mice. This work will lead to important advances in our understanding of the mechanisms coordinating NSC homeostasis in the young and old brain, and may uncover to reveal novel approaches to treat cognitive decline during normal aging and neurodegenerative disease.