People : Trainees
Predoctoral Fellows
Christopher Chou, Department of Human Genetics (MSTP), 9/1/09 – present. (Mentor: Tom Glaser, Co-mentor: Donna Martin). Chris received a Bachelor of Science degree in Bioengineering from the University of California @ Berkeley.
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.
Ann Grosse, Department of Cellular and Molecular Biology, 9/1/08 – present. (Mentor: Deborah Gumucio, Co-mentor: Ben Margolis). Ann received her Bachelor of Science degree in Biochemistry from Denison University in Granville, OH.
Research Project: Understanding the Role of Wnt5a in Epithelial Polarity and Organization During Intestinal Organogenesis. My research project is the study of both intestinal organ development as well as abnormal intestinal growth. The Wnt5a null mouse has obvious defects in processes of villus emergence and intestinal length; further study of this model will likely reveal critical new information not only about intestinal organogenesis, but potentially also leading to further understanding of congenital short bowel syndrome.
Kenneth Krill, Cellular and Molecular Biology Program (MSTP), 9/1/09 – present. (Mentor: Gary Hammer, Co-mentor: John Kim). Ken received a B.S. degree in Biology from the University of Michigan.
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). Emily received a Bachelors Degree in Biology and Music from Central Michigan University.
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.
Kathryn (Kaia) Skaggs, Neuroscience Program, 9/1/08 – present. (Mentor: Donna Martin). Kaia received an M.S. degree in the UM Neuroscience Program in 2006.
Research Project: Regulation of Spinal Interneuron Development by the Olig2-related Transcription Facto Bhlhb5. This project proposes to study how neural stem and progenitor cells give rise to motor neurons (MNs) and interneurons (INs) in the spinal cord. Errors in the process of assigning specific cell-type identity to the progenitor cells that generate neuronal and glial cell types in the CNS during development result in devastating congenital abnormalities. Loss of survival or function of these cell types underlies neurological conditions such as spinal ataxias, spastic disorders, spinal muscular atrophies, ALS, and Kennedy’s disease as well as spinal cord injuries. While a great deal of attention has been focused on describing the formation and function of MNs, recent studies have shown that several classes of excitatory and inhibitory spinal INs that regulate MN activity are critical for normal motor functions. The mechanisms that lead to IN generation in most regions of the CNS, however, are not well understood. In my proposed research, I will examine the function of a newly described transcription factor, Bhlhb5, in the generation of spinal INs. An understanding of how factors such as Bhlhb5 control the differentiation of specific IN cell types should yield insights into developmental mechanisms that lead to proper CNS function as well as causes of congenital abnormalities. In addition, this line of research may help to identify therapeutic targets to ameliorate these defects, and provide a foundation for current and future studies seeking to use stem cell-based therapies to treat neurological injuries and diseases. The experimental approaches proposed span the disciplines of genetics, cellular and molecular biology, biochemistry, and developmental biology to study mechanisms and cellular interactions that permit embryonic stem cells to generate the distinct cell types and functional circuits in the spinal cord necessary for coordinated movement.
Postdoctoral Fellows
SunJung Kim, Ph.D., Department of Internal Medicine, 10-1-09 – 9/30/10. (Mentor: Yuan Zhu). Sun Jun received a Ph.D. degree in 2008 from Seoul National University, Korea.
Research Project: The Role of the Tumor Suppressor Gene Adenomatous Polyposis Coli (APC) in the Development of the Cerebral Cortex. During the cortical development, regulation of proliferation and differentiation of neural stem cells (NSCs) and their progeny is essential for precisely establishing cortical lamination. The purpose of this research is to seek fundamental knowledge about how NSCs give rise to the highly organized six-layer cortex and if dysfunction of certain genes affects cortex development. I hypothesize that Adenomatous Polyposis Coli (APC), a negative regulator in b-catenin/Wnt signaling, is essential for the differentiation of NSCs to intermediate neural progenitor cells (INPs), and deregulated high levels of b-catenin expression causes disruption of cerebral cortex in Apc-deficient brains.
Christopher LaPensee, Ph.D., Department of Molecular and Integrative Physiology, 9/1/09 – present. (Mentor: Jessica Schwartz, Co-mentor: Jiandie Lin). Chris received his Ph.D. degree from the University of Cincinnati in 2006.
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.
Research Project: Mechanism of Mechanical Load-induced Gene Regulation in Osteoblast.
Bone has the unique property of being able to modify its structure and mechanical strength in response to dynamic loads. Osteoblasts and osteocytes in bone are surrounded by interstitial fluid within the medullary cavity and bone canaliculi. During dynamic loading of bone, displacement of interstitial fluid exposes cells to fluid flow shear stress (FFSS), which activates genes necessary for osteoblast differentiation and bone formation. Essentially nothing is known about how these mechanical signals are translated into changes in osteoblast gene expression/differentiation. Our objective in this study is to discover a mechanism of mechanical load-induced gene expression in osteoblasts. We hypothesize that mechanical signal stimulates protein kinase cascades including ERK/MAPK, resulting in translocation of the kinases to the nucleus where it binds RUNX2, a transcription factor in bone development, previously bond to regulatory regions of specific genes. From these chromatin sites, kinases initiate changes of chromatin structure by phosphorylaing chromatin substrates including RUNX2 and histones as well as by acetylating histone leading to increase transcription.
Eiichi Miyasaka, M.D., Department of Surgery, 7/1/08 – present. (Mentor: Daniel Teitelbaum, Co-mentor: Deborah Gumucio). Eiichi received his M.D. degree from the University of Michigan in 2006.
Research Project: Distraction Enterogenesis: Molecular Mechanisms of Intestinal Growth Control. Short-bowel syndrome (SBS) is a condition where the small intestinal length is less than that required for proper nutrient absorption needed for survival. The condition can occur in pediatric and adult populations, and may be due to congenital processes, or acquired through the loss of large amounts of small intestine due to inflammatory conditions or ischemic events. A novel treatment method under investigation is lengthening of the bowel through distraction forces. Preliminary porcine data has shown promise in that the bowel subjected to distraction forces increased in length, and had a proportionately increased absorptive capacity as well. However, the mechanisms which promote distraction enterogenesis are unknown. Preliminary data showed a significant up-regulation of several factors including Indian hedgehog, desmin and vimentin in these lengthened segments. The increased desmin and vimentin potentially supports a Wnt-mediated signalling pathway, as these factors are exclusively expressed in the mucosa of developing intestine during increased Wnt expression. The marked change in expression of these factors may help drive the formation of the crypt-villus axis. My projects will attempt to quantify the effects of distraction forces by examining certain morphometric parameters including crypt depth, villus height, and mucosal thickness. Functional capacity will also be examined using an Ussing chamber. We will also be examining the optimal ways to apply distraction forces to the bowel in cooperation with the Department of Engineering. After quantifying the effects, expression of growth-related factors will be tested after disrupting iHH expression. Other projects include identifying changes in cytokine expression and extent of regulatory T-cells in mice receiving TPN.
Therese Roth, Ph.D., Department of Cell & Developmental Biology and Life Sciences Institute, 9/1/08 – present. (Mentor: Yukiko Yamashita). Therese received her Ph.D. degree in 2007 from the University of Michigan, Department of Cell & Developmental Biology.
Research Project: The Role of Insulin Signaling in the Regulation of Germline Stem Cells. A steady supply of adult stem cells is critical to maintain differentiated cells at the appropriate level of homeostasis. Stem cells can divide asymmetrically so that one daughter cell remains undifferentiated to maintain the stem cell population while the other begins to differentiate. If the stem cell population is depleted, differentiated cells cannot be replaced, while overproliferation of stem cells can cause tumors to develop. An increase in tumor formation and cancer is associated with aging. This research project which studies the effect of insulin signaling on germline stem cells, is at the interface of stem cell biology, aging and cancer. There is a relationship between insulin signaling and aging/longevity that is inversely correlated with reproductive fitness. Conditions which are favorable for increased longevity, for example nutrient deficiency, often result in decreased reproduction. Conversely, increased numbers of progeny are correlated with decreased lifespan. The Drosophila male germline stem cell niche is an ideal model system to use to study stem cell interaction because the niche and germline stem cells are easily identified and the cell cycle pathway has been well-characterized. We are able to follow the stem cell niche both in fixed testes and varying ages as well as live cell imaging. Conclusions reached through studying this pathway may then be used as a basis to study stem cell-niche interactions in other model systems.