Medical Scientist Training Program (MSTP)

Individual Predoctoral Fellowship Awards

 
 

Current Students with Active Fellowships

Taylor Thompson NIH NRSA F31 Fellowship for a project entitled "Transcriptional Regulatory and Cell Differentiation Influences of an Endocrine Disrupting Chemical" (Sponsor, John Greally, Genetics)

Michelle Gulfo NIH NRSA F31 Fellowship for a project entitled "Assessing dopaminergic modulation of an associative circuit within the dentate gyrus" (Sponsor, Pablo Castillo, Neuroscience)

Meera Trivedi NIH NRSA F31 Fellowship for a project entitled "Characterizing Novel Regulations of Dendritic Tiling in C. elegans" (Sponsor, Hannes Buelow, Neuroscience)

Jamie Moore NIH NRSA F31 Fellowship for a project entitled "Unraveling Mechanisms of Plasmacytoid Dendritic Cell Priming by CD169+ Macrophages in Severe Murine Malaria" (Sponsor, Gregoire Lauvau, Microbiology & Immunology)

Adam Spitz NIH NRSA F30 Fellowship for a project entitled "Direct Small Molecule Activation of Pro-apoptotic BAK" (Sponsor, Evris Gavathiotis, Biochemistry)

Hayden Hatch NIH NRSA F31 Fellowship for a project entitled "Transcriptional regulation, neuronal development, and function of the mushroom body in a Drosophila model of intellectual disability" (Co-Sponsors, Julie Secombe and Nicholas Baker, Neuroscience/Genetics)

Joshua Weinreb NIH NRSA F30 Fellowship for a project entitled "Uncovering the Role of the DEAD Box Helicase Ddx41 in Hematopoiesis" (Sponsor,  Teresa Bowman, Developmental & Molecular Biology)

Rosiris Leon-Rivera NIH NRSA F31 Fellowship for a project entitled "Molecular Mechanisms of Increased Risk of Racial and Ethnic Minorities for HIV Associated Neurocognitive Disorders" (Sponsor, Joan Berman, Pathology)

Todd Rubin NIH NRSA F31 Fellowship for a project entitled "Examining sex as a predictor of outcomes across multiple levels of head trauma" (Sponsor, Michael Lipton, Neuroscience)

Niloy Iqbal NIH NRSA F30 Fellowship for a project entitled "Tumor Suppressor pRb is a Novel Target for Hypothalamic Inhibition of Diet Induced Obesity"(Sponsors, Liang Zhu and Streamson Chua, Jr., Developmental & Molecular Biology)

Kristin Palarz NIH NRSA F31 Fellowship for a project entitled "Serotoninergic modulation of cerebellar circuitry" (Sponsor, Kamran Khodakhah, Neuroscience)

Peter John NIH NRSA F30 Fellowship for a project entitled "B7x in Cancer: Mechanisms and Therapies" (Sponsor, XingXing Zang, Microbiology & Immunology)

Richard Piszczatowski NIH NRSA F30 Fellowship for a project entitled "Investigating the role of Nol3 in normal and malignant hematopoiesis" (Sponsor, Ulrich Steidl, Cell Biology)

Jeet Biswas NIH NRSA F30 Fellowship entitled "The sequence recognition, structure and function of the IMP family of mRNA binding proteins" (Sponsor, Robert Singer, Anatomy & Structural Biology)

Sean Healton NIH NRSA F30 Fellowship entitled "Epigenetic activity of normal and cancer-associated mutant H1 linker histones" (Sponsor, Arthur Skolutchi, Cell Biology)

Cary Weiss NIH NRSA F30 Fellowship entitled "MicroRNA-22 and the microRNA-22/tet2 network as regulators of the cell fate decision in hematopoietic stem cells and in the development of myelodysplastic syndrome" (Sponsor, Keisuke Ito, Cell Biology)

     
     

    Current Students with Completed Fellowships

    Nelson Gil, NIH NRSA F31 Fellowship entitled "The molecular basis of receptor-ligand recognition on the immunological synapse" (Sponsor, Andras Fiser, Systems & Computational Biology)

    Erik Hasenoehrl NIH NRSA F30 Fellowship for a project entitled "Targeting terminal respiratory oxidation in Mycobacterium tuberculosis: A novel investigation of Cytochrome bd oxidase function" (Co-Sponsors, Michael Berney & William Jacobs, Microbiology & Immunology)

    Ruth Howe, NIH NRSA F30 Fellowship entitled "Characterizing the Novel Protein C15ORF65" (Sponsor, Ulrich Steidl, Cell Biology)

    Liane Hunter NIH NRSA F31 Fellowship entitled "Identifying Biomarkers that Modify Outcomes in Soccer Heading" (Sponsor, Michael Lipton, PhD in Clinical Investigation)

    Joshua Mayoral NIH NRSA F31 Fellowship for a project entitled "Secreted effectors of Toxoplasma gondii bradyzoites" (Sponsor, Louis Weiss, Pathology)

    Marika Osterbur, NIH NRSA F30 Fellowship entitled "Extra-coding features of mRNA are essential for hERG channel function" (Sponsor, Thomas McDonald, Molecular Pharmacology)

    Karin Skalina, NIH NRSA F30 Fellowship entitled "Optimization of non-ablative focused ultrasound therapy for tumor immunity" (Sponsor, Chandan Guha, Pathology)

    Current Students Who Previously Held Individual Predoctoral Fellowships 

    Justin Wheat NIH NRSA F30 Fellowship entitled "Uncovering Transcriptional Regulation of a Master Hematopoietic Transcription Factor at Single Molecule Resolution" (Sponsor, Ulrich Steidl & Robert Singer, Cell Biology and Anatomy & Structural Biology)

    Michael Willcockson, NIH NRSA F30 Fellowship entitled "Regulators of the erythroid terminal differentiation decision and their connection to the cell cycle" (Sponsor, Art Skoultchi, Cell Biology)

 
 

Abstracts of Recent Projects

Taylor Thompson - ABSTRACT: One major group of environmental toxicant that affect humans negatively are endocrine disrupting chemicals (EDCs). These chemicals interfere with the body’s natural hormone regulation leading to a range of human diseases. Our research focuses on the EDC tributyltin (TBT), a chemical frequently used as a pesticide and plastic stabilizer. TBT has major adipogenic effects when exposed in utero or in adult multipotent stem cells. Previously published data have demonstrated that TBT exposure promotes differentiation of mesenchymal stem cells (MSCs) into adipogenesis, and also increases their lipid content, representing both numerical and qualitative effects on adipocytes. Mechanistically, TBT has been found to bind to the ligand-binding domain of the peroxisome proliferator-activated receptor gamma (PPARg) transcription factor (TF), which is known to form a heterodimer with the RXR TF when activated, promoting a transcriptional reprogramming of MSCs to commit them to adipogenesis. MSCs can differentiate into a number of lineages, including muscle, bone, cartilage and fibrocystic cells. When a cell undergoes transcriptional reprogramming, the sites at which the TFs bind change, reflected by alterations of the distributions of loci of open chromatin. In this project, we propose to differentiate MSCs to both adipocytes and myocytes, initially using the cell culture conditions known to promote specific differentiation of MSCs. We will map the loci of open chromatin and test gene expression in these samples, allowing us to identify TFs mediating these differentiation pathways by searching for motif enrichment corresponding to known TF binding sites. With this information available, we can then use the same approaches to test how TBT causes transcriptional reprogramming, which should reveal whether the process is identical or involves a different set of TFs. Finally, we will apply the new CellTagging approach to test cells at multiple stages of differentiation to myocytes to test whether TBT exposure affects only undifferentiated MSCs, or can also cause transdifferentiation of cells already developing in the myogenic lineage. These new insights into the mechanism of action of TBT will be valuable in understanding how EDCs have their disease- causing effects. We will also get insights from TBT into how we a small molecule can mediate ‘epigenetic therapy’, influencing transcriptional reprogramming but in a way that is targeted to specific genomic locations. Under the mentorship of Drs. John Greally and Paul Frenette, I will accomplish these goals while developing new skills in developmental biology and genetics. Additionally I will gain valuable experiences in presenting, networking, and manuscript writing, all of which are essential as I train to become and independent investigator and physician-scientist.

Joshua Weinreb - ABSTRACT: Myelodysplastic syndromes (MDS), a group of pre-malignant bone marrow failure syndromes arising from defects in hematopoietic stem cells (HSCs), are amongst the most common hematological malignancies of the elderly with ~30% progressing to acute myeloid leukemia (AML). Recently, loss-of-function germline and somatic mutations in the DEAD-box Helicase 41 gene (DDX41) have been identified in patients with MDS and AML, and are thought to contribute to disease pathogenesis. Both germline and somatic DDX41 mutations are thought to promote hematopoietic deregulation and leukemogenesis. Although a strong clinical correlation is found between mutations in DDX41 and MDS, the in vivo role of DDX41 in hematopoiesis has not been elucidated. To address this question, we will characterize hematopoiesis in a zebrafish ddx41 loss-of-function mutant. Our preliminary studies indicate that ddx41 mutants develop neutropenia and anemia. This animal model will allow us to elucidate the in vivo role of Ddx41 in normal hematopoiesis and the underlying mechanism for any defects. DDX41 has been implicated in splicing and shown to associate with components of the spliceosome including Splicing Factor 3B, subunit 1 (SF3B1), the most commonly mutated splicing factor in MDS. Additionally, MDS/AML patient samples with DDX41 mutations displayed errors in mRNA splicing that typically occur when components of the spliceosome are defective. Although these data point towards a role for DDX41 in splicing, it is still unknown if splicing aberrations contribute to the observed abnormalities in DDX41-mutated hematologic diseases. Using ddx41-deficient zebrafish will permit us to delineate the functionally relevant early molecular events leading to blood cell defects when ddx41 is mutated, which is anticipated to provide novel insight into the origins of MDS. In this proposal, we will use our novel in vivo model of Ddx41-deficiency to test the hypothesis that Ddx41 is critical for normal hematopoiesis via regulation of splicing, and that malfunctioning of this process contributes to the hematological defects seen in DDX41-mutated MDS/AML. In Aim 1, we will determine which blood populations require Ddx41 and which functional domains of Ddx41 are required for healthy hematopoiesis. In Aim 2, we will elucidate connections between DDX41 and SF3B1 using protein and genetic interaction studies. Combined these studies will reveal insights into the pathophysiology of DDX41-mutated MDS/AML.

Rosiris Leon-Rivera - ABSTRACT: Approximately 37 million people worldwide are living with HIV. HIV enters the CNS within 10 days of peripheral infection, with development of HIV Associated Neurocognitive Disorders (HAND) in ~50% of infected people despite ART. This is due to host/viral inflammatory and toxic factors within the CNS promoting neuronal injury. Studies have shown increased risk and incidence of HIV infected Hispanics for HAND compared to Whites. Molecular mechanisms underlying this increased risk have not been extensively studied. One mechanism by which HIV enters the CNS is by transmigration of infected monocytes across the blood brain barrier (BBB), establishing CNS HIV reservoirs, and inducing inflammation and neurotoxicity. A mature monocyte subset expressing the LPS receptor, CD14, and FcγIII receptor, CD16, is key to HIV neuropathogenesis, increased in the peripheral blood of HIV-infected people, and preferentially infected with HIV. We showed that CD14+CD16+ monocytes from HIV-infected people transmigrate preferentially across our human BBB model to CCL2 and CXCL12, chemokines elevated in the CNS of HIV-infected people. We also showed that CD14+CD16+ monocytes from HIV-infected people with HAND transmigrate in greater numbers to CCL2 than those from people with normal cognition. We showed that an antagonist to CXCR7, a recently identified CXCL12 receptor on monocytes, blocks CXCL12-mediated transmigration of specifically CD14+CD16+ monocytes from HIVinfected people, and we propose this as a therapeutic target to reduce their entry into the CNS. HIV DNA copies/106 PBMC from HIV-infected people, specifically within CD14+CD16+ monocytes, correlate with HAND. Using cultured CD14+CD16+ monocytes, we showed that monocytes harboring HIV (HIV+) preferentially transmigrate across the BBB to CCL2 as compared to uninfected but HIV-exposed monocytes, and that this selective advantage is due, in part, to increased junctional proteins JAM-A and ALCAM. However, there are no studies addressing whether CXCL12-mediated transmigration of mature monocytes, nor whether CXCL12-mediated transmigration specifically of HIV+CD14+CD16+ monocytes, correlate with HAND in Hispanics. Monocytes contribute to peripheral immune activation in HIV-infected people. Once CD14+CD16+ monocytes enter the CNS, they produce host/viral toxic factors that promote neuronal damage and HAND. We hypothesize that: 1. In a select cohort of HIV-infected Hispanics on ART, Hispanics with HAND, compared to those with normal cognition, have a higher percent of peripheral CD14+CD16+ monocytes expressing CCL2, CXCL12, TNF-a, and/or IL-6, and have higher levels of these mediators; 2. CD14+CD16+ monocytes from this cohort, particularly those harboring HIV, will preferentially transmigrate to CXCL12, and this will correlate with HAND; 3. Preferential transmigration of HIV+ monocytes to CXCL12 will be blocked with antibodies to JAM-A and ALCAM, and an inhibitor to CXCR7; 4. Hispanics with HAND will have higher HIV DNA copies/106 PBMC compared to Whites with HAND, contributing to their increased risk for HAND.

Niloy Iqbal - ABSTRACT: Obesity is a significant worldwide disease. The vast majority of obese patients contain higher levels of leptin in the circulation, which can be modeled in mice given high fat diet to promote diet induced obesity. Positive energy imbalance (causing obesity) in the presence of higher leptin levels indicates reduced or ineffective leptin action. Hypothalamus neurons are likely the most important leptin target cells that regulate energy balance, as leptin receptor knockout in the hypothalamus induces same degrees of obesity as leptin receptor deficiency in the whole body. It is thought that high fat diet can produce pro-inflammatory by-products in the circulation to impair hypothalamic neuron homeostasis. Neuron homeostasis is a healthy balance of post-mitotic quiescence, survival, and regeneration, and healthy hypothalamus neurons are the material basis for leptin to maintain energy balance. The tumor suppressor pRb is a central regulator of post-mitotic quiescence, survival, regeneration and differentiation. These are the fundamental aspects of cellular (and neuronal) homeostasis. In tumorigenesis, pRb is often functionally inactivated via phosphorylation by cyclin dependent kinases (CDKs). Reactivating pRb by inhibiting its kinases has been a successful cancer therapy rationale, and several CDK4/6 selective inhibitors have recently been approved by the FDA to treat cancers expressing wild type pRb. We discovered that high fat diet induces pRb phosphorylation in mediobasal hypothalamus (MBH) anorexigenic POMC neurons, inactivating pRb and activating E2F1 target gene expression in normally quiescent POMC neurons. Our study demonstrated that stereotaxic injection into the MBH to express an un-phosphorylatable pRb significantly inhibited diet induced obesity in mice. We further demonstrated that FDA approved CdDK4/6 selective inhibitor Abemaciclib, administered by intracerebral ventricular (ICV) or oral delivery, can also inhibit DIO. We propose (Aim 1) to determine molecular mechanisms by which central CDK4/6 inhibition enhances the hypothalamic energy balance circuit to inhibit DIO; (Aim 2) to determine the physiological contexts by which Abemaciclib inhibits DIO and further the pre-clinical analysis for their re-purposing as FDA approved obesity therapeutics. Successful completion of the above aims will shed new light on the etiological causes of obesity, and uncover novel therapies for obesity treatment and train the applicant for a successful career as a physician-scientist.

Richard Piszczatowski - ABSTRACT: Hematopoiesis relies on the proper function of hematopoietic stem and progenitor cells (HSPCs), in their capacity for both self-renewal and differentiation. Genetic lesions in these cell populations can give rise to myeloid malignancies including myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). Myeloproliferative neoplasms, which result in the expansion of mature myeloid compartments, commonly harbor aberrations or mutations involving the JAK/STAT signaling pathway. Mutations in JAK2, CALR, and MPL are found in the majority of MPN cases, however cooperating co-driver mutations and disease modifiers are relatively poorly understood. Current treatment options for Philadelphia-chromosome-negative (Ph-) MPNs provide symptomatic relief and do not significantly alter overall survival. Moreover, leukemic transformation to AML is a common occurrence in Ph- MPN patients, and is thought to be due to acquisition of additional mutations which ultimately lead to a dramatic reduction in patient survival. The process of leukemic transformation of MPN to AML still remains unclear, and gaining insight into the molecular mechanisms of this phenomenon may provide openings for new interventions for preventing disease progression. We have discovered that loss of the Nol3 gene in mice leads to an MPN-like disease closely resembling primary myelofibrosis (PMF). Paradoxical to its canonical functions in repressing apoptosis, deletion of Nol3 results in an increased expansion and cycling of HSPCs in the bone marrow and spleen, suggesting a novel role for Nol3 within the hematopoietic system. Our analyses show that Nol3 is frequently downregulated or deleted in patients with PMF and other myeloid malignancies, and our data provides a link between Nol3 expression and JAK/STAT activation in MPN and AML cells, implicating Nol3 in the JAK/STAT signaling pathway. Our proposal seeks to (1) characterize the molecular role of Nol3 in hematopoiesis by defining molecular functions and subcellular localization, as well as identifying functional binding partners, (2) relate Nol3 loss to human disease by dissecting the role of Nol3 within the JAK/STAT pathway and identifying critical functional domains, and (3) gain insight into cooperativity between Nol3 loss and mutational drivers in MPN and transformation to AML. Our study will not only provide a novel and robust model for studying myeloid malignancies, but will also help define for the first time a role for Nol3 as a myeloid tumor suppressor and key component of the JAK/STAT signaling pathway. More importantly, our studies will also link Nol3 to human myeloid malignancy, which will provide a deeper understanding of the molecular pathogenesis of disease.

Jeet Biswas - ABSTRACT: In humans, insulin like growth factor 2 (IGF2) mRNA binding proteins (IMPs) have been shown to be poor prognostic indicators in cancer. Work from our lab and others indicate that the two most distantly related members, ZBP1 and IMP2, accomplish this by playing drastically different roles within cells. ZBP1 (IMP1) participates in cellular organization, motility and metastasis and knockout mice are developmentally delayed and embryonic lethal. Interestingly, IMP2 knockout mice display prolonged lifespan and resistance to obesity through upregulation of mitochondrial metabolism. Work from our lab suggests that these cellular effects are mediated by the unique RNAs targets of these highly conserved and highly homologous proteins. This recognition of RNAs by IMP members is dictated by strict rules and highly conserved binding elements within the RNA target sequences. To understand how these proteins utilize their consensus sequences to guide the fate of the cell we propose a number of structural and functional studies. After determining the consensus element for IMP2 I will query the genome to identify targets of IMP2 and compare them to published ZBP1 targets. To determine how the difference in RNA preference is generated between the two proteins, I have used NMR spectroscopy to begin solving the structure of IMP2 bound to its consensus elements. By determining which amino acids of IMP2 interact with each of the binding elements, and comparing to the solved ZBP1 structure, I will understand how these proteins generate target specificity. Directed mutagenesis will then be used to interconvert the binding of each RNA binding protein. To gain mechanistic insight into how IMP2 regulates cellular metabolism, I use my determine target sequences to study its role as a trans-acting factor for mitochondrial RNA localization. A number of studies have isolated mRNAs that are preferentially localized and translated near the surface of the mitochondria (many of which are putative IMP2 targets). Through a combination of super registration and high speed live cell imaging I hope to tease apart the individual contributions of ribosomal translocation and IMP2 towards mRNA localization onto the mitochondrial surface. By understanding if this process is a one step co-translational process or if it is a two step sequential RBP regulated process, we can better understand how translational regulation of mitochondrial proteins can regulate metabolic function, both in healthy and diseased states. I propose a multifaceted approach to understand how the IMP family (and possibly other KH domain containing RBPs) generate sequence specificity through subtle changes in the structure of its RNA recognition element. Our approach will accomplish this by determining targets which IMP2 recognizes and by understanding how these lead to a unique role in metabolic regulation. As IMP family members have been shown to be upregulated in numerous cancers and confer poor prognosis, it is likely that the role of these RBPs in oncogenesis is an important and previously unmet area for investigation.

Awards

 
 
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