Jessica Wang

Mapping Genetic Contributions to Cardiac Pathology Induced by Beta-Adrenergic Stimulation in Mice

Background—Chronic stress-induced cardiac pathology exhibits both a wide range in severity and a high degree of heterogeneity in clinical manifestation in human patients. This variability is contributed to by complex genetic and environmental etiologies within the human population. Genetic approaches to elucidate the genetics underlying the acquired forms of cardiomyopathies, including genome-wide association studies, have been largely unsuccessful, resulting in limited knowledge as to the contribution of genetic variations for this important disease. Methods and Results—Using the &bgr;-adrenergic agonist isoproterenol as a specific pathological stressor to circumvent the problem of etiologic heterogeneity, we performed a genome-wide association study for genes influencing cardiac hypertrophy and fibrosis in a large panel of inbred mice. Our analyses revealed 7 significant loci and 17 suggestive loci, containing an average of 14 genes, affecting cardiac hypertrophy, fibrosis, and surrogate traits relevant to heart failure. Several loci contained candidate genes which are known to contribute to Mendelian cardiomyopathies in humans or have established roles in cardiac pathology based on molecular or genetic studies in mouse models. In particular, we identify Abcc6 as a novel gene underlying a fibrosis locus by validating that an allele with a splice mutation of Abcc6 dramatically and rapidly promotes isoproterenol-induced cardiac fibrosis. Conclusions—Genetic variants significantly contribute to the phenotypic heterogeneity of stress-induced cardiomyopathy. Systems genetics is an effective approach to identify genes and pathways underlying the specific pathological features of cardiomyopathies. Abcc6 is a previously unrecognized player in the development of stress-induced cardiac fibrosis.

Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model

We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls.

The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits.

The Hybrid Mouse Diversity Panel (HMDP) is a collection of approximately 100 well-characterized inbred strains of mice that can be used to analyze the genetic and environmental factors underlying complex traits. While not nearly as powerful for mapping genetic loci contributing to the traits as human genome-wide association studies, it has some important advantages. First, environmental factors can be controlled. Second, relevant tissues are accessible for global molecular phenotyping. Finally, because inbred strains are renewable, results from separate studies can be integrated. Thus far, the HMDP has been studied for traits relevant to obesity, diabetes, atherosclerosis, osteoporosis, heart failure, immune regulation, fatty liver disease, and host-gut microbiota interactions. High-throughput technologies have been used to examine the genomes, epigenomes, transcriptomes, proteomes, metabolomes, and microbiomes of the mice under various environmental conditions. All of the published data are available and can be readily used to formulate hypotheses about genes, pathways and interactions.

DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States

RATIONALE Only a small portion of the known heritability of cardiovascular diseases, such as heart failure, can be explained based on single-gene mutations. Chromatin structure and regulation provide a substrate through which genetic differences in noncoding regions may affect cellular function and response to disease, but the mechanisms are unknown. OBJECTIVE We conducted genome-wide measurements of DNA methylation in different strains of mice that are susceptible and resistant to isoproterenol-induced dysfunction to test the hypothesis that this epigenetic mark may play a causal role in the development of heart failure. METHODS AND RESULTS BALB/cJ and BUB/BnJ mice, determined to be susceptible and resistant to isoproterenol-induced heart failure, respectively, were administered the drug for 3 weeks via osmotic minipump. Reduced representational bisulfite sequencing was then used to compare the differences between the cardiac DNA methylomes in the basal state between strains and then after isoproterenol treatment. Single-base resolution DNA methylation measurements were obtained and revealed a bimodal distribution of methylation in the heart, enriched in lone intergenic CpGs and depleted from CpG islands around genes. Isoproterenol induced global decreases in methylation in both strains; however, the basal methylation pattern between strains shows striking differences that may be predictive of disease progression before environmental stress. The global correlation between promoter methylation and gene expression (as measured by microarray) was modest and revealed itself only with focused analyses of transcription start site and gene body regions (in contrast to when gene methylation was examined in toto). Modules of comethylated genes displayed correlation with other protein-based epigenetic marks, supporting the hypothesis that chromatin modifications act in a combinatorial manner to specify transcriptional phenotypes in the heart. CONCLUSIONS This study provides the first single-base resolution map of the mammalian cardiac DNA methylome and the first case-control analysis of the changes in DNA methylation with heart failure. The findings demonstrate marked genetic differences in DNA methylation that are associated with disease progression.

Liberals, the progressive left, and the political economy of postwar American science: the National Science Foundation debate revisited.

Apres la seconde guerre mondiale, on observe, aux Etats-Unis, une relation entre la science et la politique a la Fondation Scientifique Nationale, combinant a la fois des scientifiques liberaux et de droite

Deletion of MLIP (muscle-enriched A-type lamin-interacting protein) leads to cardiac hyperactivation of Akt/mammalian target of rapamycin (mTOR) and impaired cardiac adaptation.

Background: MLIP (muscle enriched A-type lamin-interacting protein) is a unique protein of yet unknown function. Results: MLIP impacts cardiac activity of Akt/mTOR pathways and is associated with and required for precocious cardiac adaptation to stress. Conclusion: MLIP might be a new cardiac stress sensor. Significance: These findings provide the first insight into the role of MLIP in vivo. Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation. Mlip−/− mice exhibited normal cardiac function despite myocardial metabolic abnormalities and cardiac-specific overactivation of Akt/mTOR pathways. Cardiac-specific MLIP overexpression led to an inhibition of Akt/mTOR, providing evidence of a direct impact of MLIP on these key signaling pathways. Mlip−/− hearts showed an impaired capacity to adapt to stress (isoproterenol-induced hypertrophy), likely because of deregulated Akt/mTOR activity. Genome-wide association studies showed a genetic association between Mlip and early response to cardiac stress, supporting the role of MLIP in cardiac adaptation. Together, these results revealed that MLIP is required for normal myocardial adaptation to stress through integrated regulation of the Akt/mTOR pathways.

A systems genetics approach identifies Trp53inp2 as a link between cardiomyocyte glucose utilization and hypertrophic response

Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the gene Trp53inp2 as a cardiomyocyte glucose utilization-specific factor. Trp53inp2 gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude that Trp53inp2 serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content.NEW & NOTEWORTHY Here, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identify Trp53inp2 as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content.

Operationalizing Precision Cardiovascular Medicine: Three Innovations

For precision medicine to become a reality, we propose 3 changes. First, healthcare deliverables must be prioritized, enabling translation of knowledge to the clinic. Second, physicians and patients must be convinced to participate, requiring additional infrastructure in health systems. Third, discovery science must evolve to shift the preclinical landscape for innovation. We propose a change in the fundamental relationship between basic and clinical science: rather than 2 distinct entities between which concepts must be translated, we envision a natural hybrid of these approaches, wherein discovery science and clinical trials coincide in the same health systems and patient populations. Even the generally progressive physician can be unsure and perhaps even skeptical about how precision medicine will fit into daily practice. In our view, precision medicine is personalized clinical care informed (primarily) by measurements of the genome, epigenome, proteome, transcriptome, metabolome, and microbiome. Precision medicine should result in a more healthy life with less disease burden, and it should be delivered on an individualized basis. Many therapies fail when they are tested in large animal models1,2 or when transitioning from phase I to phase II clinical trials,3,4 leading to a decrease in the number of new drugs making it to market.5 Despite improvements based on guideline adherence, cardiovascular disease remains the leading killer and a tremendous financial burden on the nation. Implementation of precision medicine will require collaboration across the spectrum of research and healthcare delivery, including funding agencies, insurers, academic medical centers, private hospitals and consumer ‘omics providers, and the potentially underappreciated relationship between patient and physician. Where to begin? How to convince patients and families to enroll? How to persuade clinicians to participate? How to add value to the health system? Who should pay? In answering these questions, we considered a new model …

Nation, Knowledge, and Imagined Futures: Science, Technology, and Nation-Building, Post-1945

With the collapse of colonial power beginning in 1945 and the emergence of new sovereign states – by 1965 the membership of the UN had increased from 51 to 117 – the post-World War II era affirmed the primacy of the nation-state, and bestowed legitimacy on local elites who secured the power to govern, and on their representatives who defended their sovereignty in international affairs. Nation-building became a watchword of the era, not just in terms of development efforts sponsored by cold war hegemons, but as an emblem of peoples’ own quest for self-determination, national liberation, and prosperity in whatever forms those always-contested objectives might take. Science and technology, emerging from WWII as major forces for destruction – and liberation – propelled their practitioners into positions of influence, and granted them new and heady access to the corridors of power at home and abroad. Political elites who sought to take advantage of the new opportunities created by the changing world order to refashion the identities and trajectories of their nations turned to the transformative potential of science and technology to fill out the contours of imagined futures. This volume examines how this process unfolded by exploring the diverse meanings and projects attached to science and technology in contexts tied to nation-building, state formation, and the long-term struggles of societies to meet human hopes and needs within the confines of the nation-state structure and a contentious international order.1 A great deal has of course been written about the engagement of science and technology with state power after World War II. Existing accounts have tended to concentrate on the quests for advanced weaponry, high technology, and large scientific establishments that came to define the symbolic and literal meanings of power in the nuclear age. Cold war competition has loomed large in these histories, given the significance of atomic weapons, nuclear reactors, rockets, and satellites as quintessential markers of security, modernity, and national prowess. Powerful states deployed such dual-use systems both to defend the realm and as forms of technological spectacle intended to secure allegiances in a dangerously divided and fluid international order. More recent scholarship on development has also drawn attention to agriculture, public health, scientific and technical aid, industrial policy, and myriad forms of social scientific investigation as modes of endeavor tied to cold war objectives.2 This work has shed much light on the scientific and technological drivers of the global reach of the superpowers, particularly from the U.S. side. We know less about how newly empowered national elites, and their ‘technocratic’ collaborators and lobbyists, called upon

A personalized, multiomics approach identifies genes involved in cardiac hypertrophy and heart failure

A traditional approach to investigate the genetic basis of complex diseases is to identify genes with a global change in expression between diseased and healthy individuals. However, population heterogeneity may undermine the effort to uncover genes with significant but individual contribution to the spectrum of disease phenotypes within a population. Here we investigate individual changes of gene expression when inducing hypertrophy and heart failure in 100 + strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). We find that genes whose expression fold-change correlates in a statistically significant way with the severity of the disease are either up or down-regulated across strains, and therefore missed by a traditional population-wide analysis of differential gene expression. Furthermore, those “fold-change” genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80–90% in neonatal rat ventricular myocytes. Our results demonstrate that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies.Personalized medicine: uncovering missed disease genesA multitude of genes associated with complex diseases are revealed by a novel personalized, as opposed to population-level, analysis of differential gene expression. While traditional investigations of the genetic basis of complex diseases assume homogeneity across individuals and identify genes differentially expressed between a diseased and a healthy population, Northeastern University and University of California Los Angeles researchers have identified a different class of disease genes that exhibit heterogeneous up and down-regulation across 100 genetically distinct mouse strains subject to a stressor inducing heart failure, but show no significant change of expression at the population level. The results, validated by in vitro knockdown, demonstrate that individualized approaches are crucial to unmask all genes involved in complex diseases, opening new avenues for the development of personalized therapies.