People : Trainees
Aaron Burberry, Molecular and Cellular Pathology, 9/1/10-present. (Mentor: Gabriel Nunez, Co-mentor: Sean Morrison). Research Project: Innate Immune Regulation of Hematopoietic Stem Cells.
Hematopoietic stem cells (HSCs) represent an ideal candidate for many clinical therapies, yet the mechanisms underlying the regulation and maintenance of HSCs remain poorly characterized. Intraperitoneal injection of the TLR4 ligand LPS induces a 5-10-fold expansion of the LSK population (Lineage- Sca1+ c-Kit+), which is enriched for hematopoietic stem and progenitor cells (HSPCs). Because most LPS preparations are contaminated with a variety of bacterial products, we hypothesized that other innate immune receptors play a role in promoting the expansion of HSPCs and HSCs during infection. My proposal aims to define the mechanisms underlying the expansion of HSCs and HSPCs and to characterize the functional capacity of HSCs to self renew following bacterial infection.
Christopher Chou, Department of Human Genetics (MSTP), 9/1/09 – present. (Mentor: Tom Glaser, Co-mentor: Donna Martin). Research Project: General Analysis of Two Novel Cases of Anophthalmia.
Over the past two years our lab has been engaged in a study involving a Caucasian family where the MAC disorder is transmitted as an autosomal dominant trait with incomplete penetrance. The proband is affected with bilateral anophthalmia as are several other more distant relatives in this large pedigree of 92 members. A number of other members show microphthalmia and colobomas. We have used linkage analysis to narrow down the region that we are investigating and have so far focused our efforts there. A second unrelated case our lab has been investigating involves a male child affected by sporadic bilateral anophthalmia with a left orbital teratoma. The teratoma is comprised mostly of chondrocytes with some neuronal remnants. Karyotypic analysis reveals a normal 46,XX karyotype thus defining a case of XX sex-reversal. He also presents with unilateral cryptorchidisim, and hypoplasticity of the cerebellar vermis and corpus callosum (Dandy-Walker Syndrome). Our studies here are focused on trying to identify the genetic causes of the MAC phenotypes in both cases.
Kenneth Krill, Cellular and Molecular Biology Program (MSTP), 9/1/09 – present. (Mentor: Gary Hammer, Co-mentor: John Kim). Research Project: Study on the Role of Dicer in Adrenal Development and Maintenance.
My project aims to study the role of microRNAs in adrenal development and maintenance using an in-vivo model. Due to the very nature of microRNAs – their abundance, redundancy, and potentially pleiotrophic effects – fully deciphering their role in organ development will require expertise from multiple disciplines ranging from molecular biology to bioinformatics. Furthermore, microRNA research has been rapidly expanding in recent years, and numerous examples of microRNA involvement in human disease have been described, shifting these small RNAs from esoteric cellular curiosities to targets of genuine clinical interest. Current diseases of the adrenal gland pertinent to organ development and maintenance include those involving organ dysfunction, dysplasia, and neoplasia. There is currently little information regarding the role of microRNAs in these adrenal diseases. We therefore foresee this proposal as an initial step in furthering the understanding of these small RNAs in not only the development of the adrenal, but its pathogenesis as well.
Emily Petty, Molecular, Cellular and Developmental Biology Program, 9/1/09 – present. (Mentor: Gyorgyi Csankovszki, Co-mentor: Yali Dou). Research Project: Regulation of C. elegans Dosage Compensation by Histone Variant H2A.Z/HTZ-1.
The proposed work centers on the widely conserved chromatin components, histone variant H2A.Z and the Set1 histone methyltransferase complex (Set1C). H2A.Z is essential for the development of all multicellular eukaryotes tested. Set1-like complexes methylate histone H3 at lysine 4, a mark important for proper gene activation in all species studied. We are studying these components in the developmental process of dosage compensation using the model organism C. elegans. Dosage compensation equalizes sex-linked gene expression between sexes and is an essential transcription program intitated at a precise time in the development of worms, flies, and humans. Previously we found that H2A.Z functions in C. elegans dosage compensation. We hypothesize the C. elegans Set1C coordinates with H2A.Z to promote proper dosage compensation and acetylation of H2A.Z is important for its dosage compensation function. We are taking an interdisciplinary approach to test our hypotheses by combining genetic, cytological, and biochemical approaches. This project will contribute to our understanding of the regulation of coordinated changes in gene expression at the fundamental level of chromatin.
Becky Simon, Cellular and Molecular Biology Program, 9/1/10 – present. (Mentor: Ormond MacDougald, Co-mentor: Robert Kennedy). Research Project: Taste Receptor Activity as a Regulator of Adipogenesis and Adipocyte Metabolism.
The goal of my research project is to determine the role of sweet taste receptors in the regulation of adipogenesis and adipocyte metabolism. Adipose tissue is a metabolically active endocrine organ that utilizes nutrient sensing pathways to determine the availability of excess energy for lipid storage. Taste receptors have recently been implicated as one such nutrient sensing mechanism because these receptors bind nutritive substances as their cognate ligands. I have observed that sweet taste receptors are expressed in adipose tissue, where their activation has effects on both adipogenesis and adipocyte metabolism. Future goals of this proposal will focus on both determining mechanisms of sweet taste receptor activation in adipocytes and utilizing in vivo models to evaluate the physiological contribution of taste receptor activation to glucose and lipid homeostasis.
Filip Bednar, M.D., Department of General Surgery, 7/1/10 – present. (Mentor: Diane Simeone, Co-mentor: Marina Pasca di Magliano). Research Project: Cancer Stem Cells in Genetically Engineered Mouse Models of Pancreatic Adenocarcinoma.
Pancreatic cancer is a deadly disease with limited treatment options, which are further hampered by the advanced stage of disease present in most patients. Our laboratory identified a cancer stem cell subpopulation in primary human pancreatic cancers with the cell surface marker phenotype CD44+CD24+ESA+. These cells were highly tumorigenic and appear to have dysregulated developmental pathways. Current chemoradiotherapy modalities appear to spare this cancer stem cell subpopulation. The study of cancer stem cells in human tumors is limited by difficulty routinely accessing human tissues and the inability to study the disease process as it progresses in a systematic way. Mouse models of pancreatic cancer exist which now allow the study of tumor initiation and development. It is the aim of this project to identify and characterize the cancer stem cell subpopulation in the Pdx-1-Cre, LSL-KRASG12D, LSL-TRP53 mouse model of pancreatic adenocarcinoma. Isolation of these cells would allow for the study of cancer stem cell contribution to the early stages of intraepithelial neoplasia and adenocarcinoma formation, a question that cannot be directly addressed by studying human tumors.
Christopher LaPensee, Ph.D., Department of Molecular and Integrative Physiology, 9/1/09 – present. (Mentor: Jessica Schwartz, Co-mentor: Jiandie Lin). Research Project: The Role of Bc16, a Novel Transcriptional Regulator, in Adipogenesis.
Adipose tissue growth involves an increase in adipocyte size and the formation of new adipocytes from precursor cells during a process called adipogenesis. Understanding the molecular basis of adipogenesis may lead to the development of therapies to treat adipose tissue-related disorders, such as obesity, diabetes, and metabolic syndrome. The adipogenic program involves coordinated transcriptional activation and repression of adipocyte genes. B cell lymphoma 6 (Bcl6) is a potent transcriptional repressor that well-studied for its role in the regulation of gene expression during B cell differentiation in germinal centers, but its actions in non-lymphoid tissues are poorly understood. My laboratory recently detected Bcl6 in adipocytes. My finding that Bcl6 expression increases in differentiating adipocytes suggests novel transcriptional mechanisms for regulation of genes that change during adipogenesis. I am developing knockdown and overexpression models in vitro and in vivo in order to advance our understanding of the role of Bcl6 in genetic programs associated with adipogenesis.
John K. Mich, Ph.D., Life Sciences Institute, 9/1/10 – present. (Mentor: Sean Morrison, Co-mentor: Jack Parent). Research Project: The Role of SCF-Kit Signaling in the Regulation of Adult Neural Stem Cell Function.
Neural stem cells reside in the brain where they create neurons and regenerate lost cells from injuries such as stroke. Little is known about their micoenvironment, or “niche”. We hypothesize that Stem cell factor (SCF), which regulates other stem and progenitor cell types, also directly regulates neural stem cells and is an important component of the neural stem cell niche. To test this hypothesis we will utilize existing mouse alleles that enable conditional ablation of SCF (Scffl) and clear observation of SCF-expressing cells with GFP (ScfGFP). First we will globally disrupt SCF in the adult mouse and test whether SCF is important for neural stem cell-mediated neurogenesis under physiological conditions. Second we will combine global ablation of SCF with a standard mouse model of stroke to test whether SCF is important for endogenous post-stroke repair. Third we will chart the expression of ScfGFP in the brain to find potential sources of neurogenic SCF, and systematically ablate these sources using tissue-specific recombination of Scffl to determine the important source of SCF for neural stem cell function. These experiments will directly demonstrate the roles and architecture of SCF-Kit signaling in neural stem cells.
Christopher N. Vlangos, Ph.D., Department of Pediatrics and Communicable Diseases, 7/1/10 – present. (Mentor: Catherine Keegan). Research Project: Understanding the role of the Danforth’s short tail mouse mutation in proper mammalian development.
My research focuses on understanding the mechanisms that lead to birth defects affecting caudal structures in humans using mouse mutations as a model. The Danforth’s short tail (Sd) mouse first appeared as a semi-dominant spontaneous mutation in an inbred colony at Stanford University in the 1920s. The phenotype of heterozygous animals includes unilateral kidney agenesis, vertebral anomalies, and a shortened and kinked tail. Homozygous Sd mice are more severely affected with bilateral renal agenesis, lack of tail, vertebral anomalies, spina bifida, lack of urogenital and anal openings, and persistence of the cloaca. Homozygous mice are born live but die within 24 hours of birth. I am currently using next generation sequencing methods to identify the mutation causing the Sd phenotype. The phenotypic characteristics of homozygous Sd mice are comparable to those seen in human patients with caudal regression syndrome, cloacal exstrophy, and VACTERL association. Thus, the Sd mouse is an excellent model for identification of novel genes responsible for human disorders.
Hebao Yuan, Ph.D., Department of Cell & Developmental Biology and Life Sciences Institute, (Mentor: Yukiko M. Yamashita). Research Project: The regulation of asymmetric stem cell division by centrosome orientation checkpoint.
Adult stem cells are critical for tissue homeostasis, especially for short-lived differentiated cell populations, such as blood, skin, and sperm cells. A hallmark of stem cells is the ability to give rise to daughter cells committed to differentiate, while maintaining the potential to self-renew. Asymmetric cell division is a common strategy used by stem cells to achieve the balance between self-renewal and differentiation. Perturbation of this balance can lead to either tumorigenesis by overgrowth of stem/stem-like cells, or tissue degeneration by depletion of stem cells. Drosophila germline stem cells (GSCs) provide a useful model system in which to study the function and regulation of adult stem cells. Drosophila male GSCs and the niche in which they reside have been identified and can be studied at single-cell resolution. Using Drosophila male germ stem cells (GSCs) as a model system, I aim to elucidate the molecular and cellular mechanisms regulating the asymmetric stem cell division. In particular, I will investigate the centrosome orientation checkpoint that ensures asymmetric stem cell division.
Xiaofeng Zhao, Ph.D., Molecular and Behavioral Neuroscience Institute, 9/1/10-8/31/11. (Mentor: Daniel Goldman, Co-mentor: Jack Parent). Research Project: An Investigation on the Role of Cytokine Crlf1a in Zebrafish Retina Regeneration.
Our project aims to understand the basic mechanisms underlying Muller Glia dedifferentiation and retina regeneration in zebrafish. We anticipate that these studies will suggest novel strategies for stimulating retina regeneration in mammals. The project best fits the Organogenesis Training Program area “Organ/Tissue Maintenance and Replacement”.
Injury or disease of the mammalian retinal often leads to lost sight that cannot be repaired. In stark contrast, zebrafish respond to retinal damage by mounting a robust regenerative response that culminates in restored vision. We hypothesize that the mechanisms underlying zebrafish retina regeneration can be used to suggest novel strategies for repairing the damaged or diseased mammalian retina. Zebrafish offer an ideal system for studying retina regeneration, not only because they mount a robust regenerative response following retinal injury, but also because their genome has been sequenced and they are amenable to molecular and genetic approaches.
Our lab recently showed that Muller Glia in the zebrafish retina are able to dedifferentiate into multipotent retinal progenitors that can regenerate all major retinal cell types following injury. I recently discovered a secreted cytokine related factor that may represent one of the earliest responses of Muller Glia to retinal injury. My preliminary data has shown that this factor is necessary for tuba1a:GFP expression in dedifferentiated Muller Glia and is likely to play a crucial role in Muller Glia dedifferentiation. During the execution of this project I will be applying the techniques of molecular and cellular biology to unravel mechanisms of retina regeneration. The broad and diverse training I will receive during the course of this project should serve me well in my future scientific endeavors.