COBRE Center for Stem Cells and Aging | Lifespan

TheCOBRE 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 Lifespans 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.

COBRE Phase II aims to:

Patrycja Dubielecka, PhDMentors: Sharon Rounds, MD and Philip Gruppuso, MD

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. Dubieleckas 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.

Olin D. Liang, PhD

Olin D. Liang, PhDMentors: Wentian Yang, MD, PhD and James Padbury, MD

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.

Jill A. Kreiling, PhD

Jill A. Kreiling, PhDMentors: Susan Gerbi, PhD and Eric Morrow, PhD

Dr. Kreilings research investigatesthe 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 Alzheimers 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. Kreilings 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. Kreilings lab will perform a set of experiments designed to determine the role of increased RTE expression with age in loss of NSC function.

Ashley Webb, PhD

Ashley Webb, PhDMentors: Gilad Barnea, PhDand Richard N. Freiman PhD

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. Webbs 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.

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.

Comparative Molecular Evaluation of Acute Myeloid Leukemia Blasts and their Microenvironment Changes at Diagnosis and Through TherapyDiana O. Treaba, MDMentor: Peter Quesenberry, MD

Aging, fat tissue, and inflammation: translating autoimmune responses into therapeutic interventionsMarco De Cecco, PhDMentor: John Sedivy, PhD

Mesenchymal stem cell derived vesicles therapy for mitigation of acute radiation syndromesSicheng Wen, MD, PhDMentor: Peter Quesenberry, MD

Genetic and metabolic mechanisms of quiescence in stem cellsNathalie Oulhen, PhDMentor: Gary Wessel, PhD

SHP2 regulation of cartilage stem cells for articular cartilage anti-degeneration and regenerationLijun Wang, PhDMentor: Wentian Yang, MD, PhD., Douglas Moore, MS

Redefining the murine hematopoietic stem cell population in marrowLaura Goldberg, MD, PhDMentor: Peter Quesenberry, M

Read more here:
COBRE Center for Stem Cells and Aging | Lifespan