The divisions research program is located in the Harvard Institutes of Medicine Building on the 6th and 7th Floor.

Dr. Battinelli joined the Hematology Division in 2008 after completing her fellowship at the Beth Israel Deaconess Medical Center. Her research focuses on the role of the platelet in the process of angiogenesis. It is estimated that more than 500 million people worldwide could benefit from treatments that regulate angiogenesis. Platelets contain many pro- and anti-angiogenic factors; however, their role in angiogenesis is not well characterized. Recently, Dr. Battinelli and her colleagues have shown that platelets store these pro- and anti-angiogenic regulatory proteins in separate distinct alpha granules that are differentially released. These observations have broad implications for platelet biology, suggesting an important role for platelets beyond their well-recognized contribution to hemostasis. Dr. Battinelli is interested in defining how platelets acquire, store, transport, and deliver these angiogenic regulatory proteins and how anti-angiogenic therapies influence this process.

The main focus of the research in Dr. Berliner’s laboratory has been on the dissection of the molecular pathways involved in differentiation of granulocytes. Early studies focused on understanding the transcriptional regulation of neutrophil-specific gene expression. This has expanded into studies of the disruption of myeloid gene expression in specific granule deficiency, myelodysplasia (MDS), and acute myeloid leukemia (AML), as well as dissection of the abnormalities of neutrophil function seen in a variety of neutrophil disorders. More recent studies are also focusing on the role of cellular stress responses in the disruption of hematopoietic cell differentiation in myelodysplasia.

Another set of studies focus on the role of inflammatory cytokines in the anemia of the elderly and in modulating the natural history of MDS. The central hypothesis of these studies is that in the absence of nutritional deficiency, anemia in the elderly usually reflects a proinflammatory state with an associated anemia of inflammation. Furthermore, these inflammatory changes also have an impact on the degree of anemia seen in patients with MDS.

The long-term goal of this laboratory is to understand the mechanism of infection by enveloped viruses. Previously, we have identified receptors for several retroviruses and investigated how these proteins activate the virus entry machinery. Recently, we discovered that endosomal cysteine proteases are essential host factors for Ebola virus infection. The roles of these proteases in spread and pathogenesis of Ebola and other hemorrhagic fever viruses are now being investigated. Also, specific inhibitors of these proteases are being developed as anti-Ebola virus drugs.

The Ebert laboratory is based at Brigham and Women’s Hospital, with links to the Dana-Farber Cancer Institute, Broad Institute, and Harvard Stem Cell Institute. The primary focus of the laboratory is the biology and treatment of hematologic malignancies, with a particular focus on myelodysplastic syndrome.

After receiving her PhD in Endocrinology from the Federal University of Rio de Janeiro (Brazil), Dr. Grozovsky joined Dr. Hoffmeister’s Laboratory to investigate the role of glycans on platelet clearance and hemostasis. Dr. Grozovsky’s research unveiled the mechanism by which the hepatic Ashwell Morell Receptor (AMR) removes desialylated (sialic acid depleted), senile platelets and regulates TPO synthesis in the liver by recruiting JAK2 and STAT3 signaling. The identification of this feedback mechanism shed light into the longstanding mystery of steady-state TPO regulation (Nat Medicine 2015). This outstanding work was selected as a Plenary talk in the 56^th ASH meeting and granted the 2014 Mary Rodes Gibson Memorial Award, as the highest scoring abstract by a trainee in the field of Thrombosis and Hemostasis. Now Dr. Grozovsky’s laboratory investigates the role of glcans in the physiology of platelets as it relates to cancer, cardiovascular and myeloproliferative diseases.

Understanding the mechanisms controlling platelet production is key to the development of new strategies to treat patients with thrombocytopenia due to congenital disorders or cancer treatment. Our laboratory investigates the role of protein glycosylation during megakaryocyte differentiation and platelet production with particular focus on a specific glycan structure (lactosaminyl glycan). We study how glycans decorating megakaryocyte adhesion receptors tightly regulate megakaryocyte interaction with the bone marrow environment and therefore platelet production.

The Italiano Lab has had a long-standing interest in identifying and characterizing the biochemical and molecular mechanisms underlying the production of platelets. Megakaryocytes generate platelets by remodeling their cytoplasm into long cytoplasmic extensions called proplatelets, which serve as assembly lines for platelet production. Dr. Italiano and his group have identified cytoskeletal pathways that are required for platelet biogenesis. Elucidation of the cell biological and signaling pathways that culminate in the formation of platelets should yield strategies for accelerating platelet counts in patients with thrombocytopenia.

In addition, the Italiano Lab has investigated the role of blood platelets in regulating new blood vessel development, or angiogenesis. They have established that pro- and anti-angiogenic regulatory proteins are stored in separate and distinct alpha-granules in platelets, and that these distinct populations of alpha-granules are susceptible to differential release. Significant efforts are now underway in the lab to identify the mechanisms by which angiogenic regulatory proteins are packaged into distinct granules and to establish the pathways that regulate their selective release. A better understanding of the mechanisms by which platelets regulate angiogenesis should yield strategies for pro- and anti-angiogenic therapy.

Dr. Machlus’s laboratory focuses on understanding both the mechanism of proplatelet initiation and platelet formation from their precursor cells, megakaryocytes, and also the hemostatic qualities of the platelets being released. Simply put, both platelet quantity and quality. Dr. Machlus is uniquely poised to address this question due to her specialized training; as a PhD student with Dr. Alisa Wolberg at UNC she investigated relationships between procoagulant plasma proteins, platelet activity, and thrombus formation and as a postdoctoral fellow with Dr. Joe Italiano at Harvard, the major focus of her research was to identify cell biological pathways leading to platelet formation from megakaryocytes. This unique perspective allows Dr. Machlus to assess both platelet quantity and quality, beginning at differentiation of megakaryocytes from hematopoietic stem cells, through megakaryocyte maturation, and ultimately to platelet production.

Dr. Machlus’s laboratory is especially interested in revealing how different disease states alter megakaryocytes, and how these changes are ultimately manifested in their platelet progeny. Specifically, Dr. Machlus is interested in how different mediators of inflammation, such as the cytokine CCL5, alter hematopoietic stem cell differentiation, megakaryocyte maturation, and ultimately platelet production. These studies can lead to novel approaches to treat thrombocytopenia through manipulation of platelet number and function by targeting their precursor cells, megakaryocytes. This would provide a significant advantage over current thrombocytopenia treatment options that address only platelet number and take 12 days to reach maximum efficacy.

Recurrence of cancer in the form of metastatic disease accounts for more than 90% of cancer deaths; however, tumor metastasis is considered an inefficient process whereby disseminated tumor cells remain undetected for protracted periods of time. Remarkably little is known about processes that serve to convert indolent tumors – such as the metastases that disseminate from a primary tumor – into overt, life-threatening tumors. Our research is focused on identifying systemic factors that contribute to tumor progression and finding ways to interdict their function. It is our hope that such information will ultimately lead to new therapies to treat cancer patients.

The Mullally lab focuses on translational cancer research in the field of myeloid malignancies, with a focus on myeloproliferative neoplasms (MPN). The laboratory studies the biology, genetics, and therapy of myeloid cancers using primary human samples, murine models and multiple in vitro model systems. They use standard biochemical assays, proteomics, multi-parameter flow cytometry, in vivo functional genomics (including CRISPR) and next generation sequencing technologies. Current projects in my laboratory are focused on the biology of mutant calreticulin in MPN, hematopoietic-stromal interactions in the context of myelofibrosis, the differential molecular dependencies of disease-propagating stem cells in myeloid cancers, identification of heritability alleles for familial MPN. The laboratory is actively expanding currently. Please contact us if you are an exceptionally motivated post-doctoral candidate interested in joining my group.

Research in the Paw lab is focused on using zebrafish and mammalian genetics to understand erythroid development. In particular, the Paw lab is interested in factors that are critical in differentiation to erythroid lineage, especially those involved in intracellular trafficking of iron and heme.

The use of hematopoietic stem cells (HSCs) transplant, for the treatment of bone marrow failure syndromes and leukemia, is limited due to the availability of matching donor(s) and/or numbers of HSCs. To circumvent these issues, we are analyzing new sources and factors regulating emergence and development of HSCs from hemogenic endothelium. We have identified cell-intrinsic and cell-extrinsic factors that stimulate HSC production from endothelial cells. We expect to establish a new recipe to stimulate HSCs from hemogenic endothelial cells. The long term goal of our study is to regenerate patient-derived hemogenic endothelial cells for the treatment of patients with genetic blood disorders and cancers.

Platelets are essential for hemostasis, and platelet transfusions are widely used to treat patients with inherited or acquired thrombocytopenia. Consequently, the limited availability of donor platelets owing to their 5-day shelf life, immunogenicity of PLT products, and risk of sepsis due to bacterial contamination are of serious clinical concern. New strategies for generating platelets in vitro from non-donor dependent sources are necessary to obviate these risks and meet transfusion needs. My Research Goals are to develop a bio-mimetic system to study the cell biological and molecular pathways involved in platelet production, and produce useable numbers of clinically viable human platelets for infusion.

We are accomplishing this by generating a microfluidics platform that recapitulates the human bone marrow cellular environment and vasculature under physiologically relevant shear forces. Polydimethylsiloxane (PDMS) biochips fully integrate megakaryocyte and platelet biology with extracellular matrix composition and stiffness, hemodynamics and microvascular geometry to study the physiological determinants of platelet formation.