12 research outputs found
Regulation of synaptic function and plasticity by cyclin-dependent kinase 5
Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2013.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis. "February 2013." Page 192 blank.Includes bibliographical references.The neuronal serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) is activated by its regulatory subunit, p35, to post-translationally modify substrates through phosphorylation. In this thesis, I provide several lines of evidence that Cdk5 plays a critical role in synaptic function and plasticity. First, we characterized the function of Cdk5 in learning and memory by region-specific Cdk5 ablation. From multiple Cdk5 conditional knockout mouse models, we determined that Cdk5 is essential for memory formation and synaptic plasticity. Loss of Cdk5 in the hippocampus disrupts the cAMP pathway due to increased phosphodiesterase proteins. This dysregulation of cAMP signaling can be attenuated by a phosphodiesterase inhibitor to restore levels of protein phosphorylation, synaptic plasticity, and memory. Moreover, forebrain-specific deletion of Cdk5 affected multiple aspects of behavior that can partially be rescued by lithium treatment. We next identified the N-type calcium channels as a presynaptic substrate of Cdk5. We described how Cdk5-mediated phosphorylation of the N-type calcium channel increased calcium influx and channel open probability. This in turn enhanced the association of the N-type calcium channel with the active zone protein RIM1, which impacted vesicle docking and neurotransmission. Finally, we identified the postsynaptic density protein Shank3 as a Cdk5 substrate and observed that Cdk5-mediated phosphorylation of Shank3 plays a critical role in maintaining dendritic spine morphology and synaptic plasticity. Our collective results demonstrate a central role for Cdk5 in regulating both presynaptic and postsynaptic functions and provide better insight into how specific targets of Cdk5 can impact a general mechanism underlying synaptic transmission, synaptic plasticity, and cognitive function.by Susan C. Su.Ph.D.in Neuroscienc
Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers
https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd
Analysis of heritability and shared heritability based on genome-wide association studies for 13 cancer types
Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl², on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.11 page(s
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types
BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types
BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
Background: Studies of related individuals have consistently
demonstrated notable familial aggregation of cancer. We aim to estimate
the heritability and genetic correlation attributable to the additive
effects of common single-nucleotide polymorphisms (SNPs) for cancer at
13 anatomical sites.
Methods: Between 2007 and 2014, the US National Cancer Institute has
generated data from genome-wide association studies (GWAS) for 49 492
cancer case patients and 34 131 control patients. We apply novel mixed
model methodology (GCTA) to this GWAS data to estimate the heritability
of individual cancers, as well as the proportion of heritability
attributable to cigarette smoking in smoking-related cancers, and the
genetic correlation between pairs of cancers.
Results: GWAS heritability was statistically significant at nearly all
sites, with the estimates of array-based heritability, h(l)(2), on the
liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the
combined heritability of multiple smoking characteristics, we calculate
that at least 24% (95% confidence interval [CI] = 14% to 37%) and
7% (95% CI = 4% to 11%) of the heritability for lung and bladder
cancer, respectively, can be attributed to genetic determinants of
smoking. Most pairs of cancers studied did not show evidence of strong
genetic correlation. We found only four pairs of cancers with marginally
statistically significant correlations, specifically kidney and testes
(rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and
pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic
lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung
(rho = 0.35, SE = 0.14). Correlation analysis also indicates that the
genetic architecture of lung cancer differs between a smoking population
of European ancestry and a nonsmoking Asian population, allowing for the
possibility that the genetic etiology for the same disease can vary by
population and environmental exposures.
Conclusion: Our results provide important insights into the genetic
architecture of cancers and suggest new avenues for investigation
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types
Initial invasive or conservative strategy for stable coronary disease
BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used
Health-status outcomes with invasive or conservative care in coronary disease
BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline