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Studying Sex Differences in Biomedical Research

2012 PRESIDENTIAL EARLY CAREER AWARD IN SCIENCE AND ENGINEERING (PECASE)Over the past two decades, we have learned a great deal about how men and women respond differently to medications. This knowledge came after a concerted effort in the early '90's to increase the number of women in NIH-funded clinical research. Today, just over half of NIH-funded clinical research participants are women. Unfortunately, experimental design in cell and animal research has not always followed suit. An over-reliance on male animals and neglect of attention to the sex of cells can lead to oversight of key differences that should be guiding clinical studies, and ultimately, clinical practice. As part of a larger NIH initiative, the Office of Strategic Coordination recognized an opportunity to provide substantial insights into sex differences through enhancements to a number of programs. 


Genotype-Tissue Expression (GTEx) 

Genotype-Tissue Expression ProgramThe Common Fund’s GTEx program provides data on how human DNA variation correlates with variation in gene expression levels, uncovering valuable insights into the mechanisms of gene regulation and how perturbations in gene expression may be related to various diseases. Although data are being collected from male and female donors, dedicated analysis of sex differences had not been planned.

 

GTEx supplements:

Drs. Christopher Brown and Barbara Englehardt (supplement to R01-MH-101822)
This supplement aims to understand the impact of sex specificity on gene expression. The investigators will identify gene transcripts and splice sites that are differentially expressed in males and females and will look for sex-based differences in gene expression levels that correlate with genetic variation.

Drs. Nancy Cox and Emmanouil Dermitzakis (supplement to R01-MH-101820 and R01-MH-101814)
This supplement is developing and using novel methods to characterize the role of sex in gene transcription, including transcriptional variation, sex-specific gene expression, and the relationship of sex-biased transcriptome biology to disease. 

Dr. Andrew Feinberg (supplement to U01-MH-104393)
This supplement investigates sex differences in gene expression within the brain that may be controlled by modification to DNA or DNA-associated proteins, called epigenetic modifications. 

Dr. Michael Snyder (supplement to U01-HG-007611)
This supplement aims to identify sex-specific differences in protein expression and sexually dimorphic biological pathways.

Dr. Barbara Stranger (supplement to U01-HG-007598)
This supplement is evaluating proteins across multiple tissues in many individuals, focusing on sex-biased gene expression levels, hormone signaling pathways, sex-chromosome encoded genes, and proteins implicated in complex diseases with sex-biased characteristics.


Human Health and Heredity in Africa (H3Africa) 

H3Africa LogoH3Africa , part of the Common Fund’s Global Health program, aims to enhance the capabilities and capacities of African scientists to enable a contemporary research approach to the study of the genomics and environmental determinants of disease and to use this information to improve the health of Africans and populations around the world.

H3Africa supplements:

Dr. Guida Landoure (supplement to U01-HG-007044)
This supplement is examining sex differences in psychosocial burden related to hereditary neurological disorders. Early results show that women disproportionately experience negative psychosocial consequences of such disorders, and this research aims to elucidate the factors contributing to this phenomenon and identify preventive solutions.

Dr. Michele Ramsay (supplement to U54-HG-006938)
This supplement is enhancing sample collection and analysis for two robust African cohorts, providing a rich resource to explore sex differences in adiposity and cardiometabolic diseases.


High Risk, High Reward 

High risk, high reward programThe Common Fund’s High Risk, High Reward program consists of the Pioneer, New Innovator, Transformative Research, and Early Independence Awards, each of which is designed to support exceptionally creative scientists undertaking bold and innovative research projects. These awards support paradigm-changing research in all areas within the NIH mission.

 

High Risk, High Reward supplements:

Dr. Nicole Basta (Early Independence Award, supplement to DP5-OD-009162)
This supplement aims to investigate sex-specific differences in nutritional status and markers of inflammation and their role in driving heterogeneity in immune response to vaccines that protect against meningococcal disease, tetanus, and pneumococcal disease. This research will address observed sex-specific differences in immunity, provide insight into the mechanisms by which variation in immunity is sustained in the population, and provide evidence for future policy-based decisions regarding targeted vaccination strategies.

Dr. Lauren Weiss (New Innovator Award, supplement to DP2-OD-07449)
This supplement aims to better understand sex differences in autism traits using datasets from both inherited and idiopathic cases of autism spectrum disorders. This project has potential for understanding how sex interacts with genetic variants to mediate autism risk, and may provide insight into new therapeutic approaches.


Library of Integrated Network-based Cellular Signatures (LINCS) 

NIH LINCS ProgramThe LINCS program aims to develop a “library” of molecular signatures that describes how different types of cells respond to a variety of perturbing agents.

 

LINCS supplements:

Dr. Srinivas Iyengar (supplement to U54-HG-008098)
This supplement is investigating differences in cellular signatures between male and female cardiac myocytes in response to drugs that have been shown to have sex-specific cardiotoxic effects.


Metabolomics 

MetabolomicsThe Metabolomics program aims to increase the national research capacity in metabolomics, the study of low molecular weight molecules found in cells and biological systems. Metabolomics provides a measure of the output of biological pathways, and is therefore a useful representation of the functional state of cells and biological systems.

Metabolomics supplements:

Dr. James Crapo (supplement to R01-HL-089897)
This supplement is identifying sex-specific changes associated with Chronic Obstructive Pulmonary Artery Disease (COPD) and emphysema, looking at combined effects of sex/age and sex/smoking, and investigating changes associated with menopause. This study may identify sex-specific markers for susceptibility to developing advanced COPD and emphysema.

Dr. Charles Czeisler (supplement to P01-AG-009975)
This supplement aims to investigate sex differences in how chronic sleep loss and circadian disruption independently affect metabolic health, analyzing both metabolic and lipidomic samples. 

Dr. Vicki Ellingrod (supplement to R01-MH-082784)
This supplement is investigating the influence of sex on risk for developing metabolic syndrome in males and females with schizophrenia, where women are known to be at higher risk. This research will examine metabolic signatures associated with the development of this condition, and examine whether sex differences in these signatures are evident. 

Dr. Irva Hertz-Picciotto (supplement to R01-ES-015359)
This supplement will investigate serum metabolic signatures in children with autism spectrum disorders, which demonstrate a clear sex difference in diagnosis rates. This research could provide insights into the pathology of autism spectrum disorders, reveal clues about the disproportionate sex distribution, and contribute to the identification of modifiable risk factors that could serve as targets for intervention. 

Dr. Samia Mora (supplement to R01-HL-117861)
This supplement aims to advance our understanding of lipid species that differ in men and women, including specific lipids related to high-density lipoprotein (HDL) function and statin therapy. These studies will also examine how the menopause transition affects HDL structure and function. 

Dr. Eugenia Trushina (supplement to R01-ES-020715)
This supplement is investigating sex-dependent metabolic differences in human fibroblasts derived from patients with Alzheimer’s disease. This research may uncover dynamic changes in cell metabolism associated with Alzheimer’s disease and may revel sex differences in these metabolic pathways. 

Dr. Kenneth Wright (supplement to R01-HL-109706)
This supplement is examining sex difference in the human metabolome in response to sleep deprivation, which may underlie observed sex differences in energy expenditure, food intake, hormone levels, and weight gain in response to insufficient sleep. This study will also examine whether the benefits of weekend recovery sleep are the same or different in males and females.


NIH Office of Research on Women's Health (ORWH)

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