The Cabot Lab
(7/9/14)The Cabot Lab focuses on sphingolipid metabolism as it relates to cancer growth and therapy. Sphingolipid metabolism is an area of cancer research that has risen to clinical prominence over the last 15 years. This is because ceramide, the aliphatic backbone of sphingolipids, acts as a powerful tumor suppressor, whereas its glycosylated product, glucosylceramide, catalyzed by the enzyme glucosylceramide synthase, is anti-apoptotic and a biomarker of multidrug resistance, as identified by Cabot in the mid-1990's. Acid ceramidase, another important sphingolipid enzyme regulator of cancer cell growth, has recently been identified as candidate gene for development of new cancer diagnostics and touted as a therapeutic target in metastatic cancer. Like glucosylceramide synthase, acid ceramidase dampens the tumor suppressor properties of ceramide via ceramide hydrolysis and leads to the generation of sphingosine 1-phosphate, a powerful cancer cell mitogen. Thus, sphingolipid metabolism is a dynamic process with complex orchestration, impact, and clinical applications. Importantly, these enzymes are druggable targets.
The Geyer Lab
(7/1/14)The Geyer lab is interested in how retinoic acid (RA) directs the initial steps of male germ cell development. RA regulates the sex-specific timing of meiotic initiation in mice, which in males occurs at postnatal day (P)10. However, RA signaling initiates 1 week prior, at P3-4, yet we know almost nothing about the pathways or mechanisms initiated by RA signaling and their relationship to neonatal male germ cell differentiation. We recently discovered that RA directs neonatal germ cell proliferation, ultrastructure maturation (mitochondria and Golgi biogenesis), modified timing of meiotic initiation, and the expression of differentiation markers such as STRA8 and KIT. In addition, we found that RA stimulates translation of a panel of mRNAs in differentiating spermatogonia, and this discovery is the current focus of investigations in the Geyer laboratory. We are currently using in vivo and ex vivo approaches with neonatal testis explants in combination with RA and a variety of inhibitors to understand how RA signaling enhances the translation of mRNAs encoding critical differentiation markers such as STRA8 and KIT. The identification of pathways activated by RA will provide a significant advance in our understanding of how cell fate decisions are made at the initiation of spermatogenesis and provide insight into the etiology of testicular cancers and male infertility.
(9/22/14)The Funai Lab studies cellular processes by which skeletal muscle handles substrate overload during metabolic stress. As skeletal muscle is an organ with the highest metabolic demand, metabolic changes that occur in skeletal muscle have tremendous consequences on whole-body metabolism. Specifically, we are interested in the cellular fate of lipid molecules in skeletal muscle. We utilize cell lines, genetically-modified mice and biopsies from human subjects to examine mechanisms whereby skeletal muscles develop and/or evade toxic effects of lipid influx.
The Houmard Lab
(7/30/14)The Houmard Lab's primary focus is examining how skeletal muscle metabolism is altered with conditions such as obesity, type 2 diabetes and the aging process, and how a physically active lifestyle can counteract decrements associated with these conditions. Current ongoing projects involve how fat oxidation is altered with obesity, the role of exosomes in the insulin resistance of obesity, the metabolic changes seen with gastric bypass surgery, and how exercise training can rescue the reduction in fat oxidation and insulin resistance seen with obesity.
The Huang Lab
(9/08/14)The Huang Lab is currently focusing on answering the following scientific questions: 1)whether exercise induces hypothalamic neurogenesis and 2) which particular neurons in the hypothalamus controls moving behavior. Their plan is to open a new research avenue combining the various neuroscience techniques used on transgenic animal models to determine whole body metabolism with exercise and /or nutrition intervention.
The McClung Lab
(7/25/14)The McClung Lab is focused on understanding the molecular mechanisms of angiogenesis and vascular remodeling in both physiologic and pathologic processes, including: exercise, peripheral artery disease (PAD), atherosclerosis, cardiac and cerebral ischemia, diabetes, and cancer. The lab is interested in how genetic variation may direct the integration of individual cellular responses to ischemic insult, resulting in differential manifestations of tissue pathology in both pre-clinical models and in clinical patient populations. On a deeper level, the lab is studying how single nucleotide polymorphisms affect autophagy, mitochondria, oxidative stress, and signal transduction by endothelial receptor tyrosine kinase (RTKs) in different cell types (skeletal muscle, endothelial, progenitor, smooth muscle, fibroblast). Therapeutic strategies targeting the vasculature in cardiovascular disease have met with little success, and those aimed at preventing tumor angiogenesis result in significant side effects that often result in forced cessation of therapy. The McClung lab hopes to lay the foundation for the development of novel diagnostic and therapeutic tools for tissue ischemia and aid in the refinement of current anti-angiogenic therapies for cancer. The lab currently consists of Dr. McClung (PI), Cameron Schmidt (Graduate Student). Tom Green (currently in Oncology as a Research Associate) will be joining the lab August 1.
(9/12/14)The Neufer Lab centers around mitochondria. Their research is directed at deciphering the molecular mechanisms governing mitochondrial bioenergetics and function in the context of the etiology of metabolic disease as well as disease prevention/treatment.
The Shaikh Lab
(8/26/14)The Shaikh lab currently has three major projects . 1) The first project is trying to understand how omega-3 fatty acids, modeling pharmacological intake, serve to boost B cell mediated immunity in diet-induced obesity. Obese individuals display poor responses to vaccinations and infections and therefore there is a need to develop therapeutics to enhance immunity in these individuals. We have discovered that clinical grade omega-3 fatty acids can boost the antibody response to several antigens including in response to influenza infection. We are currently trying to understand the underlying mechanisms by which omega-3 fatty acids boost B cell responses. Our focus is on specialized pro-resolving mediators and the biophysical organization of the B cell plasma membrane. This work is in collaboration with Melinda Beck at UNC-CH. 2) The second project entails trying to understand how changes in cardiolipin levels in response to differing metabolic diseases dysregulate the formation, size, and stability of cardiolipin microdomains and thereby protein clustering in the inner mitochondria membrane of cardiomyocytes. Here we are using FRET and FRAP approaches coupled with enzymatic assays and functional studies in collaboration with the Zeczycki and Brown labs. 3) The third project is a deviation from our central focus on lipids. Here we are trying to understand how SAMe, a dietary supplement, suppresses pro-inflammatory cytokine secretion in primary macrophages. Our ultimate goal here is to link how changes in the inflammatory environment with SAMe impact the progression of depression in humans, where SAMe is known to exert beneficial effects.
(9/30/16) The Spangenburg Lab is focused on elucidating novel mechanisms that regulate physiological and metabolic function of skeletal muscle. The lab employs an integrative experimental approach, in which we use cell culture and animal models to define mechanisms that we then work to translate to the human. Specifically, we have developed skeletal muscle specific-inducible knock out mice and the ability to ablate gene expression in cultured human myotubes through shRNA delivered via AV virus approach. This integrative approach allows us to examine the same loss-of function approach using in vivo animal models and cultured myotubes from humans. The lab has the ability to assess skeletal muscle function on multiple levels including ex vivo muscle force generation, isolated single muscle cells, rotorod, etc. We are able to provide a comprehensive phenotype of the skeletal muscle from a single cell level to the whole muscle level. The lab also employs a number of approaches to assess mitochondrial function including Oroboros based approaches using muscle fiber bundles or Seahorse based approaches. Finally, the lab also has significant expertise with fluorescent imaging of single muscle cells and whole muscle using confocal and two-photon based approaches. The lab is located on the fourth floor of the ECDOI and is funded by the NIH and ADA.
The Zeczycki Lab
(8/05/14)The Zeczycki Lab's focuses on determining the mechanisms of catalysis and unraveling the complexities of allosteric regulation of those multifunctional enzymes that are important to the pathogenesis of disease states. Understanding the activity and regulation of these enzymes is critical for the development of effective therapeutics which can modulate, rather than inhibit, enzyme activity. The current focus of research in our lab is directed towards two different enzymes, pyruvate carboxylase (PC) and transglutaminase 2 (TG2). The aberrant activities of these enzymes are partially responsible for the pathogenesis and exacerbation of Type 2 diabetes and neurodegenerative diseases, respectively. In order to determine the physiologically relevant kinetic, chemical and allosteric mechanisms inherent to these enzymes, our lab uses a combination of in vitro techniques to examine the unique enzymatic biochemical transformations, dynamic domain motions and inter-subunit communication pathways. These techniques, common to the fields of molecular biology, chemical biology and enzymology, include protein engineering, site-directed mutagenesis, steady-state and pre-steady-state kinetics and 1D/2D NMR.