A Conserved Role for Syndecan Family Members in the Regulation of Whole-Body Energy Metabolism

Syndecans are a family of type-I transmembrane proteins that are involved in cell-matrix adhesion, migration, neuronal development, and inflammation. Previous quantitative genetic studies pinpointed Drosophila Syndecan (dSdc) as a positional candidate gene affecting variation in fat storage between two Drosophila melanogaster strains. Here, we first used quantitative complementation tests with dSdc mutants to confirm that natural variation in this gene affects variability in Drosophila fat storage. Next, we examined the effects of a viable dSdc mutant on Drosophila whole-body energy metabolism and associated traits. We observed that young flies homozygous for the dSdc mutation had reduced fat storage and slept longer than homozygous wild-type flies. They also displayed significantly reduced metabolic rate, lower expression of spargel (the Drosophila homologue of PGC-1), and reduced mitochondrial respiration. Compared to control flies, dSdc mutants had lower expression of brain insulin-like peptides, were less fecund, more sensitive to starvation, and had reduced life span. Finally, we tested for association between single nucleotide polymorphisms (SNPs) in the human SDC4 gene and variation in body composition, metabolism, glucose homeostasis, and sleep traits in a cohort of healthy early pubertal children. We found that SNP rs4599 was significantly associated with resting energy expenditure (P = 0.001 after Bonferroni correction) and nominally associated with fasting glucose levels (P = 0.01) and sleep duration (P = 0.044). On average, children homozygous for the minor allele had lower levels of glucose, higher resting energy expenditure, and slept shorter than children homozygous for the common allele. We also observed that SNP rs1981429 was nominally associated with lean tissue mass (P = 0.035) and intra-abdominal fat (P = 0.049), and SNP rs2267871 with insulin sensitivity (P = 0.037). Collectively, our results in Drosophila and humans argue that syndecan family members play a key role in the regulation of body metabolism

The Role of Neuroinflammation in Traumatic Brain Injury-Induced Anxiety Disorders: a possible therapeutic target

Traumatic brain injury (TBI) is a rising public health concern, with approximately 1.7 million people in the United States alone sustaining a TBI each year (Vaishnavi et al., 2009; Faul, 2010). In addition to the physical, cognitive and behavioral impairments, the long-term consequences of TBI include increased risk of neuropsychiatric disorders, and anxiety disorders are among the most prevalent (Rao and Lyketsos, 2000; Moore et al., 2006; Vaishnavi et al., 2009). In spite of increasing evidence that anxiety disorders are elevated following TBI, very little is known about the etiology of post-traumatic anxiety. Chronic neuroinflammation is now thought to contribute to the development of post-traumatic anxiety, the primary injury initiates complex cascades that can lead to secondary injury and worsened functional outcomes. These secondary cascades may contribute to the dysfunction of brain regions and neurotransmitter systems associated with anxiety following TBI. New evidence supports this hypothesis, including peripheral elevations of proinflammatory cytokines in patients with post-traumatic stress disorder (PTSD) and panic disorder (Spivak et al., 1997; Tucker et al., 2004; von Kanel et al., 2007; Hoge et al., 2009) and anxiety-like behavior (Connor et al., 1998; Cragnolini et al., 2006; Sokolova et al., 2007; Zubareva and Klimenko, 2009) when these cytokines are administered in rats. The goal of this thesis is to better understand the role of neuroinflammation in post-traumatic anxiety. The development of post-traumatic anxiety involves a number of complex molecular, cellular, neurochemical and physiological changes, and better understanding of these processes will be needed for successful treatment strategies in this population

Autonomous CaMKII Activity as a Drug Target for Histological and Functional Neuroprotection after Resuscitation from Cardiac Arrest

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of physiological glutamate signaling, but its role in pathological glutamate signaling (excitotoxicity) remains less clear, with indications for both neuro-toxic and neuro-protective functions. Here, the role of CaMKII in ischemic injury is assessed utilizing our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). CaMKII inhibition (with tatCN21 or tatCN19o) at clinically relevant time points (30 min after resuscitation) greatly reduces neuronal injury. Importantly, CaMKII inhibition also works in combination with mild hypothermia, the current standard of care. The relevant drug target is specifically Ca2+-independent “autonomous” CaMKII activity generated by T286 autophosphorylation, as indicated by substantial reduction in injury in autonomy-incompetent T286A mutant mice. In addition to reducing cell death, tatCN19o also protects the surviving neurons from functional plasticity impairments and prevents behavioral learning deficits, even at extremely low doses (0.01 mg/kg), further highlighting the clinical potential of our findings

Neuroimmune Support of Neuronal Regeneration and Neuroplasticity following Cerebral Ischemia in Juvenile Mice

Ischemic damage to the brain and loss of neurons contribute to functional disabilities in many stroke survivors. Recovery of neuroplasticity is critical to restoration of function and improved quality of life. Stroke and neurological deficits occur in both adults and children, and yet it is well documented that the developing brain has remarkable plasticity which promotes increased post-ischemic functional recovery compared with adults. However, the mechanisms underlying post-stroke recovery in the young brain have not been fully explored. We observed opposing responses to experimental cerebral ischemia in juvenile and adult mice, with substantial neural regeneration and enhanced neuroplasticity detected in the juvenile brain that was not found in adults. We demonstrate strikingly different stroke-induced neuroimmune responses that are deleterious in adults and protective in juveniles, supporting neural regeneration and plasticity. Understanding age-related differences in neuronal repair and regeneration, restoration of neural network function, and neuroimmune signaling in the stroke-injured brain may offer new insights for the development of novel therapeutic strategies for stroke rehabilitation