Detailed Research Descriptions
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Chip Aquadro
We have for over a decade been studying (often in collaboration with Prof. Mariana Wolfner) the molecular evolution and function of reproductive proteins in Drosophila and mammals. The focus has been largely on proteins involved in fertilization and that are transferred to the female during copulation, many of which are surprisingly rapidly evolving. More recently, we have studied the molecular evolution of genes involved in germline stem cell maintenance and differentiation to form gametes. We have discovered that several of the key GSC genes in Drosophila evolve at an extraordinarily rapid rate due to natural selection protein divergence between species. The functional consequences, and evolutionary mechanisms generating, this rapid protein evolution of critical GCS genes is now a significant focus of our research efforts and carried out in collaboration with Prof. Daniel Barbash. Our studies include population genetic analyses, as well as cell, developmental and reproductive assessments of function using site-specific interspecific gene transformation, and the evaluation of functional interactions with intracellular microbes, pathogens, viruses and transposable elements.
Daniel BarbashWe study Drosophila germ-line stem cell function and evolution. Some genes involved in germ-line stem differentiation show surprisingly high evolutionary rates in their protein-coding sequences. This discovery suggests that germ-line stem cells may face a continual challenge of adapting to external pathogens and internal genomic parasites such as transposable elements. In collaboration with Prof. Charles (Chip) Aquadro we are investigating the functional consequences of this gene evolution. We have additional research projects addressing the functional evolution of heterochromatin and heterochromatin-binding proteins, which also have important implications for understanding the repressive environment required to maintain stem cells.
Our laboratory focuses on the use of marrow-derived mesenchymal stem cells for skeletal tissue regeneration. We are particularly interested in identifying mechanical stimuli that are chondrogenics for stem cells and in factors that regulate mechanical adhesion of stem cells to connective tissue.
Jonathan Butcher
We seek to understand the microenvironmental cues in embryonic development that guide precursor cells toward mature phenotypes in the heart. The objective is to use this paradigm to drive the differentiation of autologously accessible stem populations toward these unique phenotypes for regenerative/therapeutic applications.
The Cohen lab is interested in the regulation of mammalian meiosis and germ cell development. Our research is primarily focused on the control of meiotic recombination by DNA repair proteins, but extending from that, we are interested in how post-meiotic gern cells acquire and maintain competence to undergo fertilization.
Once ovulated, the terminally differentiated mammalian oocyte will die if it does not bind and fuse with a sperm. If fertilization occurs, however, maternal gene products orchestrate the transformation of the egg into a totipotent zygote within hours. My lab is investigating the role that novel, highly-abundant, and egg-restricted molecules play in this reprogramming process. Additionally, we are also investigating the role of maternal epigenetic modifiers (and the histone modifications that they catalyze) in gene regulation in the egg and preimplantation embryo.
My lab provides a wide range of technical services to the department and external research organizations on and off campus in immunohistochemical (IHC) techniques including immunoperoxidase and immunofluorescence IHC, in situ hybridization, and TUNEL in a variety of species of fixed / frozen tissue, and cultured cells including embryonic or adult stem cells. The lab also provides services for preparation and cryosectioning of frozen tissues. With prior experience with stem cell research, I am very interested in all possible collaborations to develop markers for analyzing and characterizing the embryonic stem cells including iPS cells.
Stem cells have the ability to directly or indirectly promote tumor malignancy. Our lab utilizes biomedical engineering strategies to model specific microenvironmental conditions that may play a critical role in regulating the tumor-promoting potential of these cells by controlling their self-renewal, differentiation, and secretory behavior.
We have been studying a late-onset B cell immunodeficiency in the horse that causes B cell depletion from primary and secondary lymphoid tissues. Affected adult horses present recurrent bacterial infections and lack of antibody production. We have been investigating mechanisms of regulation of B cell differentiation using equine bone marrow- and fetal liver-derived hematopoietic stem cells; in addition, we have efforts toward creating a horse-mouse chimera so we can populate equine B cells in SCID mice starting from these hematopoietic stem cells. Our goal is to identify the cause of this disease and a treatment for it.
The Fortier laboratory focuses on refining the clinical application of stem cells for treatment of orthopaedic diseases. The two main clinical areas of interest are in cartilage and ligament regeneration. The goal is to use cell surface and epigenetic modification markers to identify the optimal subpopulation of stem cells for therapeutic applications.
We are developing antibodies that are specific to surface markers of ovarian and other cancer stem cells. Developed antibodies will be used to deliver nucleic acids and drugs, as well as for conjugation to nanoparticles for in vivo imaging.
We study the establishment of polarity in the early C. elegans embryo. This occurs through a series of stem-cell like divisions; the zygote divides asymmetrically producing a somatic cell and a germ-line stem cell. The germ-line stem cell divides asymmetrically three more times generating three more somatic cells and a single germ-line primordial cell. Our research focuses on the mechanistic basis for the asymmetric division of the germ-line stem cells.
The Kotlikoff lab is using stem cells to repair the injured heart. Current cell -based therapies result in modest improvement in heart function, but also risks electrical dysfunction. Experiments see to transfer cells that persist within the damage myocardium and are electrically coupled to the normal heart tissue.
The Ets transcription factor Pea3 is overexpressed in breast tumors suggesting that it plays a role in mammary oncogenesis. In the normal mammary gland, Pea3 is expressed in the epithelium of the mouse mammary anlagen commensurate with their genesis and in the stem and progenitor cells of the adult mammary gland. To understand the role of of Pea3 in mammary epithelial stem cells our laboratory takes advantage of mouse genetics and the mammary transplantation assay to determine the downstream cellular effectors of Pea3 signaling during mammary gland development.
Our laboratory is interested in elucidating the molecular basis of longevity using C. elegans and mammalian models. One of our research areas is to investigate how germline stem cells affect longevity in C. elegans. In addition, we plan to investigate how stem cell functions may be altered during aging in various mouse longevity mutants.
The Lis lab's interest lies in identifying genome-wide transcriptional activities in embryonic stem cells to help understand the transcription networks and the regulatory steps critical for the maintenance and differentiation of stem cells. As a first step, they are applying their recently developed approach for examining genome-wide distributions of engaged RNA polymerase II (Pol II) by global run-on assays and Solexa sequencing in mammalian cells, which provides unique snapshots of all transcriptionally-engaged RNA Pol II over the entire genome, including actively elongating Pol II and regulatory, promoter-proximal paused Pol II. These complete transcriptional signatures will help understand regulatory differences between pluripotent and differentiated cells at the molecular level and provide a framework for exploring the combinations of transcription factors that permit faithful reprogramming of the differentiated cells to an embryonic stem cell state, and that direct differentiation of embryonic stem cells to specialized cell types.
The major research interest in my lab is mesodermal patterning and fate specification. Specifically, we use the /C. elegans/ postembryonic mesodermal lineage as a model system to study how a single pluripotent progenitor cell proliferates and differentiates into a number of muscle and non-muscle cells. Deciphering the molecular mechanisms underlying fate specification will help us understand better how stem cells can be directed into specialized functional lineages.
We study developmental biology of the mammalian pancreas. Our current research focuses on understanding the interplay of transcriptional regulators and intercellular signals that control pancreatic cell fate determination, endocrine/exocrine lineage decisions, lineage-specific differentiation and maintenance of the distinguishing phenotypes of the hormone-producing islet cells.
Our lab focuses on using DNA as a general material building block. We have created novel DNA-based materials including dendrimers, nanobarcodes, and hydrogels that are made entirely from branched DNA through enzymatic reactions. More relevant to the stem cell community, our nanobarcodes can be used for multiplexed detection including in situ FISH. Our DNA hydrogels can be employed to culture stem cells in a 3D fashion with a total control over pore sizes, shapes and internal contents. In addition, the DNA gel is capable of producing proteins without any living organisms.
Our lab's interest in stem cell research is linked to our interest in improving in vitro models of the upper GI tract. We are working to make a model of the GI tract that includes crypt cells grown in 3D culture. Our efforts are in collaboration with Dan Luo's group who is working with DNA gel scaffolds for growing our cells. Ultimately we want to use our 3D cultures to study interactions between commensal bacteria and the upper intestine.
Understanding how molecular and cellular mechanisms controlling normal stem cells may be involved in malignant transformation is essential for development of better regenerative medicine approaches, as well as for advances in our understanding of cancer pathogenesis. Our laboratory focuses on elucidation of mechanisms by which tumor suppressor genes, microRNAs and microenvironmental factors control embryonic and adult stem cells and how aberrations in these mechanisms may lead to cancer.
Adult stem cells can be isolated, propagated, and programmed to facilitate musculoskeletal repair. This work involves transcriptional profiling of MSC and EPCs, gene directed differential pathway switching, and combinatorial approaches to transposon based stem cell transduction and cytokine suppression within orthopedic repair tissues.
My laboratory is interested in understanding of the pathogenesis of obesity and diabetes. In particularly, we are studying the control of (a) fat cell differentiation and (b) myeloid cell differentiation using animal and cell culture models.
Stem-cell related research in my lab includes: 1) The identification of mouse genes involved in proliferation or maintenance of the germline stem cell pool; 2) study of a novel gene that is required for pre-implantation mouse development and is highly expressed in embryonic stem cells but is downregulated upon differentiation; and 3) use of embryonic stem cells as tools to identify novel genes required for germline stem cells.
Our laboratory is interested in both basic and translational aspects of stem cell biology. By investigating early events in the activation of development after fertilization, we seek to understand the events leading to establishment of the pluripotency network and the genesis of embryonic stem cells in the developing blastocyst. We also study cues that guide the differentiation of pluripotent stem cells into oligodendrocyte precursors for cell therapy-based myelin regeneration in demyelinating diseases.
The Shen lab uses various experimental perturbation assays, computational modeling tools, and robustness analysis to understand asymmetric cell division. The tools and models will help re-program asymmetric stem cell division.
We study the cis and trans acting factors that control reprogramming of epigenetic states in the mouse germ line. Our goal is to understand how epigenetic marks are established, maintained and propagated to other sites in the genome and how these mechanisms are influenced by environmental variables.
My laboratory investigates stem cell-based technologies to preserve genetic diversity and to manipulate the germline. Specifically, we study testis xenografting and spermatogonial stem cell transplantation in dog and cat models. Both techniques give the practical benefit of being able to produce sperm from genetically valuable donors. In addition, they also provide models for the study of spermatogonial stem cells and spermatogenesis, and provide an opportunity to generate transgenic animals as important biomedical models for human and animal disease.
Our laboratory is interested in elucidating the basic cellular and molecular mechanisms implicated in cell fate choice and stem cell activity within tissues. We focus on adult stem cells and their interaction with the tissue of residence, and use the mouse skin as a
primary model system. Within the skin epithelia stem cells are thought to reside both in the outer epidermis and in a specialized area of the hair follicle called the bulge. The bulge is a stem cell niche thought to keep their potent resident cells in a differentiation and proliferation inhibited state. It allows external signals to selectively penetrate and instruct stem cells to migrate out and proliferate when they are needed: during the initiation of the hair follicle growth and in wounded, regenerating skin. Understanding the basic signaling pathways involved in regulating stem cells in their native tissue will help manipulate cells in culture for cell and tissue transplantation therapy.
The Weiss lab develops mouse models to study (1) stem cell genome maintenance by DNA damage checkpoint mechanisms and (2) the role of adult stem cells in lung carcinogenesis.
We are studying the molecular mechanism of retinoic acid in control of the cell cycle and differentiation. Retinoic acid is a developmental morphogen that controls embryogenesis. We are studying how it controls the cellular decisions to proliferate or not and choose a specific differentiation lineage using an immature hematopoietic precursor cell to gain insight into the pathways that it governs