Regulation of Adult Neurogenesis
The birth of new neurons in the adult brain is a remarkable discovery, and it is clear that these neurons are critical to normal brain function and disease. Indeed, adult neural stem cells hold promise for the treatment of neurodegenerative and psychiatric disorders. We have discovered a novel group of proteins (Rit and Rin) that are critical to the survival and maturation of newborn adult neurons. Through the combined use of biochemistry, molecular biology, and the analysis of a variety of transgenic mice, we hope to understand the pathways that are used during neurogenesis with the goal of applying this knowledge toward the treatment of neurodegenerative disease.
Molecular Analysis of Paramyxovirus Infection
The Dutch laboratory focuses on the entry and assembly of emerging paramyxoviruses, including identification of cellular receptors for clinically important viruses, elucidation of key elements in the promotion of membrane fusion by viral fusion proteins, and determination of viral and host factors which drive particle assembly and viral spread. Student projects in the Dutch lab include dissection of the role of host factors in human metapneumovirus assembly and entry and determination of the role of transmembrane domains in the stability and function of viral fusion proteins.
Mechanisms of DNA Repair
DNA repair is essential for normal development and heredity. In addition, many cancers are thought to arise as a result of faulty or absent repair activities. Repair enzymes must locate damaged sites embedded in a very large excess of normal DNA. To help determine how damaged sites are located, the prospective student will use molecular and biophysical methods to characterize the DNA-interactions of an important human repair enzyme.
From Biofuels to Neurodegeneration
The lab is focused on two main research areas that are linked by an enzyme family called glucan phosphatases. First, we study fundamental questions addressing the nature and mechanisms of glycogen metabolism and how misregulation of these signaling events leads to neurodegenerative epilepsy called Lafora disease (LD). This work is funded by the National Institutes of Health. Second, we study the role of glucan phosphatases in starch metabolism in plants and algae, and this work is funded by the National Science Foundation. One goal of this project is to determine how glucan phosphatases could be harnessed in starch-based industrial manufacturing and biofuels. Thus, our work uniquely links neurodegeneration with biofuels research.
- Developing a biochemical assay to monitor enzyme function in Lafora disease patients.
- Defining glucan phosphatases in plant and algal species.
Identification of miRNAs Regulated by Glucose
miRNAs are small RNA molecules that regulate translation in cells and have been implicated to play a role in many diseases. Since glucose is the major carbon and energy source for most organisms, the major goal of this project to identify miRNAs that are up- or down-regulated by glucose in order to study their function in glucose metabolism.
Using Chemical Probes to Examine Brain Lesions in Alzheimer's Disease
Alzheimer’s disease pathology includes the formation of deposits of insoluble protein aggregates in the brain. The primary component of these lesions is the peptide A-beta. However, A-beta alone is insufficient to cause the disease in animal model systems. This project involves using chemical probes to identify other, unknown, biomolecules that form the insoluble brain lesions in Alzheimer’s disease.
Synthesis of New Antineoplastic Agents
Our laboratory works with molecular biologists on the development of new “small molecule” agents of potential value for the treatment of cancer. We apply synthetic organic chemistry to the development of various heterocyclic agents that target proteins for which there are no current drugs available.
Modeling Fusion Oncoproteins in Zebrafish
Summer research in the Blackburn lab will be focused on utilizing CRISPR genome editing in zebrafish to develop new models of translocations common to pediatric leukemias. Chromosomal translocation is a hallmark of these cancers, yet the mechanisms by which the resulting fusion oncoproteins drive leukemia progression are largely unknown due to a lack of in vivo models. The student will use molecular biology techniques to create CRISPR constructs, perform genome editing in zebrafish, and optimize protocols for in vivo gene insertion events.
RNA Splicing of Genes Related to Cholesterol Homeostasis and Alzheimer's Disease
The goal of this project is to (i) identify novel splice variants in mRNAs encoding proteins implicated in cholesterol homeostasis and Alzheimers disease and (ii) evaluate the role of genetics, splicing factors and Alzheimers disease in generating these splice variants by correlating their quantities with variations in DNA sequence, levels of relevant splicing factors, and disease status. Hence, we seek to identify novel factors that modulate brain cholesterol and Alzheimer's disease risk.
Role of the Shoc2 Scaffold Protein in Cellular Function
Our research program focuses on an understanding of the molecular mechanisms through which the fundamental MAPK1/2 pathway is regulated in space and in time with the particular emphasis on the scaffolding protein Shoc2. To this end, we are using comprehensive and interdisciplinary approaches that incorporate biochemistry, cell biology, biophysical analysis, and state-of-the-art microscopy. As we discover the details of how scaffold protein Shoc2 controls specificity and distribution of MAPK1/2 signals and itself regulated by the ubiquitin system, we integrate these insights from basic research with the study of human cancer and developmental disease. We believe that a better understanding of the molecular basis of malignant transformation or congenital dysfunctions will lead not only to further advances in biology but also novel and effective cancer therapies.
Novel Antibacterials Against Mycobacterium Tuberculosis
The emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, represents a major threat to public health. There is an urgent need for the development of new and more effective anti-tubercular drugs targeting previously unexplored cellular processes. The goal of this project is to find novel classes of antimicrobial compounds active against M. tuberculosis.
Understanding the basis for broad substrate recognition in neuropeptidases, enzymes that metabolize peptides used to transmit signals between cells in the nervous system and other tissues. Development of drugs that target these enzymes as therapeutics for disorders of the nervous system and pain relief.
Role of Small RNAs in the Prader-Willi Syndrome
The Prader-Willi syndrome is the most frequent inherited cause for obesity and type II diabetes. Genetic evidence shows that the disease is caused by the loss of small nucleolar RNAs. We recently showed that some of these small nucleolar RNAs function in alternative splice site selection. The project aims to identify new targets of these small nucleolar RNAs and to understand their mechanism of action.
Characterization of Platelet Function in Blood Clotting
As the second most abundant cell in the body, platelets are critical to blood clotting. Clinically, anti-platelet drugs are used to control inappropriate clot formation, which accounts for 1 in 4 deaths worldwide. Projects in the lab focus on understanding how platelets control clot formation and determining what else platelets can do. Specific projects involve the analysis of genetically altered mice that lack elements of the platelet secretory machinery. These studies use imaging and reconstitution assays to determine the specific steps that are defective and how they affect clotting and other platelet functions.
Characterization of Intrinsically-Disordered Proteins
Over the last decade a new class of proteins, known as intrinsically disordered, has been identified. These often do not fold into a defined structure until they bind a target molecule. The prospective student will use a variety of techniques to help us express, purify, and characterize the physical behavior of calcineurin, a vital phosphatase whose critical regulatory domain is disordered until bound by the calcium-sensing protein calmodulin.
The Role of Chromatin Structural Dynamics in Gene Regulation
We have recently shown that chromatin controls gene expression not only at the initiation step but how these genes are ultimately spliced. Our recent discovery of PARP-1, a chromatin structural protein in regulating chromatin structure during transcription and splicing, underscores the importance of understanding the rules that govern the establishment of specific chromatin states in gene regulation. Studies in my lab are aimed towards understanding how PARP-1 is recruited to a particular chromatin site, what are the epigenetic modifications that regulate this recruitment and lastly what is the function of its presence at a particular location. Common techniques used are genome-wide nucleosome mapping, FRET, mutational studies, ChIP, as well as biochemical and molecular biology techniques.
Functional Importance of A Novel Family of Protein Phosphatases, PHLPP, in Regulating Tumorigenesis
My lab focuses on elucidating the functional importance of a novel family of protein phosphatases, PHLPP, in regulating tumorigenesis. We use colon cancer as a model system to study how PHLPP functions in suppressing cancer development and progression. Our recent studies indicate that PHLPP functions as a tumor suppressor by directly dephosphorylating Akt and terminating Akt-mediated oncogenic signaling. Some of the specific projects being conducted in the lab include: to study the regulation of PHLPP protein stability via ubiquitination, to identify and characterize novel substrates of PHLPP, and to elucidate PHLPP-mediated tumor-inhibiting effect in vivo. We combine biochemical and molecular biological approaches in our studies, and we have developed PHLPP knockout mouse models in the lab to further investigate the role of PHLPP in suppressing cancer growth. The results from our studies will aid in developing novel therapeutic strategies in cancer treatment by using PHLPP as a target.
Mechanistic Connections Between Diabetes and Alzheimer's Disease
Both type II diabetes (DM2) and Alzheimer's disease (AD) are significant public health problems. It has been known for several years that mid-life DM2 confers significant risk for the development of AD in later years. Our lab has recently made some exciting advances in mapping out some of the basic molecular processes that may underly this link. This project will use techniques in biochemistry, cellular and molecular biology to explore this linkage in cultured cells, particularly in primary neurons.
Examining the Role of Sumoylation in Regulating Lamin A Function
The lamin A protein plays an important role in nuclear structure and function. Our previous studies showed that normal lamin A function requires it to have a protein called SUMO-2 covalently attached to it, and lamin A mutations that prevent SUMO-2 attachment are known to cause disease in people. In this summer project, the student will perform studies that seek to understand the role of SUMO-2 attachment in regulating lamin A function while learning about lab techniques, the scientific method, the role of lamin A in cell function, and protein sumoylation.
Craig Vander Kooi
Role of Cell Surface Receptors in New Blood Vessel Formation
New blood vessel formation (angiogenesis) is critical during development and wound repair. The project involves understanding the basis for ligand/receptor interactions which stimulate angiogenesis using structural probes. Tumor angiogenesis is also required for the growth of many types of solid tumors and we are also exploring novel anti-angiogenic strategies.
Protein Misfolding Response in Lou Gehrig's Disease
The goal of this project is to determine how the protein misfolding response pathways are activated by the SOD1 mutants that are linked to Lou Gehrig's disease. We will examine the expression levels of several key proteins involved in protein misfolding response. We will also characterize the signaling pathways downstream of protein misfolding response to determine how SOD1 mutants cause cellular damages and neuronal degeneration.