Sex Differences in Brain Disorders Emerging Transcriptomic Evidence: Proceedings of a Workshop (2021) / Chapter Skim
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4 Moving Forward
4 Moving Forward
Pages 29-40
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. • The BRAIN Initiative Cell Census Project aims to build an integrated, multi-modal brain atlas as a tool to advance under standing of sex differences in the brain (Ngai)
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Understanding sex differences in the brain is one of the major challenges to be addressed as neuroscience moves forward, said Eric Nestler. This will require integrating genomic, transcriptomic, epigenetic, cellular, and circuitry data in order to understand how genome sequence influences function and how it interacts with the environment throughout life, he said.
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Recognizing that there is much more to learn about sex differences at the genetic and transcriptomic level, Stranger said studies need to be specifically designed to evaluate sex differences in healthy and diseased individuals in longitudinal cohorts across developmental time points, as well as in cell lines. BRAIN Initiative Cell Census Project One of the BRAIN Initiative's major coordinated projects, the Cell Census Project, offers opportunities to advance understanding of sex differences in the brain and how they contribute to both health and disease, said Ngai.
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. More recently, again with BRAIN Initiative funding, David Anderson and colleagues used deep sequencing single cell profiling to identify 17 transcriptionally distinct cell clusters, several of which were male or female specific (Kim et al., 2019)
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The second set of studies are more exploratory and tend to be more hypothesis driven as they assess potential sex differences at the mechanistic level, said Michelson. These studies are informed by predictions emerging from preclinical studies, what is known about the mechanism, and what is known about the differential impact of the compound in men and women.
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POLICY IMPLICATIONS OF INCORPORATING SEX AS A BIOLOGICAL VARIABLE INTO RESEARCH AND DRUG DEVELOPMENT In 2014, NIH announced that as part of its efforts to ensure rigor and transparency in taxpayer-funded research, the agency would require investigators to account for sex as a biological variable (SABV) in all funded research, said Janine Clayton, associate director for research on women's health and director of the NIH Office of Research on Women's Health (ORWH)
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. Clayton provided an overview for three of these goals and described several NIH programs designed to reach the first goal -- advancing r igorous research relevant to the health of women, including research on biological differences between females and males, sex differences in health and disease, effects of exposure on disease outcomes, and the mind–body connection as it pertains to sex and gender.
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FDA guidance3 recommends that preclinical studies include animals of both sexes. In 1998, the agency issued a regulation that required new drug applications to present safety and efficacy data by age, race, and gender; another 1998 regulation4 required annual reports for investigational new drug data to be presented by age, race, and gender.
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Vasisht described some of the recent research undertaken by FDA in the area of sex differences. For example, FDA OWH–funded researchers have used exome and RNA sequencing data to evaluate sex differences in Alzheimer's disease and have evaluated transcriptomics- and epigeneticsbased predictions of sex- and age-related susceptibilities to treatmentinduced adverse effects.
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. Laitner suggested other policy changes that could accelerate research on sex differences, including incorporating sex and gender issues into basic research and design courses; educating grant reviewers, institutional review boards, and institutional animal care review committees about appropriate ways to consider sex and gender in research designs; and overseeing the publication of research findings to ensure that sex and gender are appropriately addressed.
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For example, how do environmental factors affect the epigenome, transcriptome, and disease pathways differently in men versus women; what is the impact of lifelong changes in hormonal status; are there different longitudinal changes in the peripheral transcriptome of men and women and how do they affect disease progression and outcomes; and what sex differences are seen across multiethnic populations? To understand how these changes occur through a person's lifetime, Ertekin-Taner advocated leveraging peripheral tissue collections and longitudinal cohorts to conduct multi-omics studies, focusing on the transcriptome as well as other omics and integrating other genetic, outcome, and biomarker data.
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While there remains an open discussion in the field on areas of future research, other questions also needing to be addressed, said Nestler, include how sex differences may impact functional changes reflected in the genome sequence; interactions between the genome and environment throughout life at transcriptional, translational, post-translational, cellular, synaptic, and circuit levels; and ultimately, how these impact behavior. In addition, it would be crucial to develop resources to gain access to post-mortem human brain tissue of people who do not fall along the male/female binary, for example, transgender individuals, those who have transitioned sex, and intersex individuals, to include in this type of research, he added.
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