Arthur Palmer Arnold, PhD - US grants
Affiliations: | Integratiive Biology & Physiology | University of California, Los Angeles, Los Angeles, CA |
Area:
sexual differentiation, brain, metabolism, genetics, sex chromosomes, testosterone, estradiol, birdsongWebsite:
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The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Arthur Palmer Arnold is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1977 — 1980 | Arnold, Arthur | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Neural and Hormonal Basis of Avian Vocalizations @ University of California-Los Angeles |
0.915 |
1980 — 1983 | Arnold, Arthur | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Ontogeny of Sexually Dimorphic Neural Circuits @ University of California-Los Angeles |
0.915 |
1985 — 2000 | Arnold, Arthur P | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Steroid Influences On Neurons Involved in Behavior @ University of California Los Angeles We have recently discovered a sexually dimorphic motor nucleus, the spinal nucleus of the bulbocavernosus (SNB), which innervates penile striated muscles in male rats. The SNB and its target muscles are nearly absent in females. The proposed series of experiments will study the sexual differentiation of this behaviorally relevant motor nucleus and its target muscles. Because of the relative simplicity of neuromuscular systems, and because the SNB is likely to be intimately involved in sexually dimorphic copulatory behavior, this is an attractive model system for study of the ontogeny sex differences in central nervous structures involved in behavior. By injecting various steroid hormones into pre and post-natal rats of various ages, we will ascertain which steroids are effective in determining the presence or absence of the SNB and its target muscles, and when they exert such an action. Using steroid autoradiography, we will investigate the development of steroid accumulation in the SNB and its target muscles, and relate this to the effects of steroids on development. Using thymidine autoradiography and other histological techniques, we will study the timing of neuronal birth and development of the SNB in normal males and females, and relate this to the timing of steroid effects in this system. Using implants of steroids, we will attempt to discover the sites of steroid action on the development of this system, which will also have important implications concerning the mechanisms of steroid action. |
0.936 |
1985 — 2008 | Arnold, Arthur P | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neural and Hormonal Bases of Vocalization @ University of California Los Angeles DESCRIPTION: The long term objective of these studies is to determine the forces that cause sex differences in brain and behavior. For more than 40 years, the central concept of sexual differentiation has held that all sex differences in brain and behavior result from the peripheral actions of gonadal steroid hormones. Recent research on the neural circuit for song in the zebra finch conflicts with this classic dogma, and suggests the alternative hypothesis that some sex-specific gene products may act directly on brain to induce sex-specific neural development, independent of the action of gonadal hormones. The proposed experiments will begin to test this novel concept. (1) Two sex chromosome-linked genes, which are expressed in female but not male brain have been identified. The genes are candidates for genetic signals that induce sexual differentiation. These genes and their relatives will be cloned and characterized to determine how their expression is regulated according to sex, tissue, developmental age, and by steroid hormones. (2) Other genes, thought to be involved in sexual differentiation downstream of the initiating event, will be studied to determine when and where their mRNAs are expressed in the brain. (3) SOX genes known in other species to be involved in sexual differentiation of non-neural tissues, will be studied to determine if they are expressed in a sexually dimorphic manner. (4) Sex-specific dissociated neural cell cultures will be prepared from the brains of neonatal animals to determine if they exhibit sex differences in the expression of specific antigens and mRNAs, in order to develop in vitro model systems amenable for the study of factors influencing sexual differentiation. The proposed research will contribute significantly to an understanding of the principles of sexual differentiation of the brain and mechanisms of steroid hormone action on the brain. At issue are the molecular mechanisms by which male and female brains differ, which is highly relevant to biological basis of abnormalities of sexual differentiation, and to the explanation of sex differences in neural and psychiatric disease (e.g., Alzheimer's and Multiple Sclerosis). Moreover, the proposed studies bear strongly on the regulation of steroid hormone action on the nervous system, during reproduction and stress. |
0.936 |
1987 — 1991 | Arnold, Arthur P | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neural &Hormonal Bases of Vocalization @ University of California Los Angeles There are large sex difference in the structure and function of brain regions controlling song in passerine birds. These sex differences develop under the control of gonadal steroids. The long term objectives are to understand the cellular mechanisms by which gonadal steroids influence the development of these neural circuits that control a complex learned motor pattern. By gaining knowledge of these cellular mechanisms, we will also shed light on the neural mechanisms responsible for song learning and for the limitation of learning to an early critical period. Using castration and various treatments with steroid hormones and antihormones, we will examine which steroids act singly or in combination to alter the morphological development of the song system (numbers and sizes of neurons). Other experiments will measure steroid accumulation and projections of steroid sensitive neurons to clarify possible sites of steroid action in the control of neural development. Using thymidine autoradiography, we will assess when song system neurons undergo their last mitotic division, and manipulate steroid levels to determine if steroids regulate neuron number by altering the processes of proliferation or migration of neurons. Anatomical tract tracing techniques will map the ontogeny of interconnections between song system neurons to suggest possible times at which these neurons can have trophic interactions regulated by steroids. |
0.936 |
1990 — 1991 | Arnold, Arthur Schlinger, Barney [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Workshop On Neuroendocrine Strategies in a Tropical Environment; San Antonio, Texas, December 1990 @ University of California-Los Angeles This award will support a workshop on neuroendocrine strategies in a tropical environment in conjunction with the 101st Annual Meeting of the American Society of Zoologists in San Antonio, Texas. The workshop, organized by Professors Barney Schlinger and Arthur Arnold of UCLA, will focus on tropical ecology and its relevance to neuroendocrine mechanisms in animal physiology and behavioral ecology. The meeting will highlight ongoing research in comparative neuroendocrinology within Latin America as well as studies utilizing neotropical animals. The tropical regions of the New World are considered by many to contain the greatest biological diversity of any region on the planet. This region is currently experiencing intense pressure from rapid development, including massive deforesta- tion and destructive land-use practices, actions that will detrimentally affect animal populations. This Science in Developing Countries award will help to promote collaboration and exchange of ideas between North American and Latin American comparative neurobiologists and endocrinologists in a topic of strong mutual interest. |
0.915 |
1991 — 1992 | Arnold, Arthur Schlinger, Barney [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Estrogen Synthesis in Brain and Its Functional Role @ University of California-Los Angeles Steroid hormones profoundly influence the structure and function of the central nervous system during development and throughout the vertebrates' lifespan. While the major source of testosterone and estradiol comes from the gonads, the brain also produces steroids. Aromatase enzymes responsible for the metabolism of androgen into estrogen are localized within specific target neurons in discrete brain regions. Since aromatase is not found in testes or adrenals, Dr. Schlinger will determine whether the major source of circulating estrogen in these males is derived from aromatization of androgens in the brain. This has important theoretical ramifications because the brain may not only be a target of steroid hormones but also a major source of a circulating steroid. Dr. Schlinger will also examine the role of brain estrogen synthesis in the regulation of sex differences in brain development and function. These studies will lead to new insights in the mechanisms underlying hormone- brain interactions. Increasing our knowledge about the basic processes underlying normal neuroendocrine events will contribute towards a better understanding of birth defects that result from insufficient and/or excessive exposure to a particular steroid hormone. |
0.915 |
1994 — 1997 | Arnold, Arthur P | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Analysis of Estrogen Synthesis in the Brain @ University of California Los Angeles |
0.936 |
1998 | Arnold, Arthur | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
@ University of California-Los Angeles This award subsidizes the registration fees to allow graduate students to attend the 1998 annual meeting of the Society for Behavioral Neuroendocrinology, a new society dealing with research on hormonal interactions with brain and behavior. The meetings foster cross-disciplinary discussions of topics such as behavioral ecology, chronobiology, developmental and physiological psychology, genetics, neuroscience and cellular and molecular endocrinology. The society is in a period of rapid growth. This support will have an impact on exposing a number of students to such important cross-disciplinary research, which will be important to shaping their careers. |
0.915 |
1999 — 2000 | Arnold, Arthur | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
@ University of California-Los Angeles The proposal is to provide funds that will greatly increase the ability of graduate students to attend the 1999 annual meeting of the Society for Behavioral Neuroendocrinology. This new Society, which has a membership of over 350, fosters communication and interdisciplinary collaboration among research scientists who are studying how hormones act on the brain. These hormonal actions include: growth and maturation of the brain, the mechanisms by which we respond to stress, seasonal and other rhythmic changes in mood and behavior, effects on brain of hormones and hormone-like chemicals that are released into the environment, effects on brain of hormones involved in the control of reproduction and fertility of humans and domesticated animals, psychological effects related to stress and reproduction, etc. The Society brings together scientists who are involved at many levels of discovery, including the molecular, cellular, systems, and behavioral levels. The Society has adopted the founding principle that annual meetings will be student-friendly and will emphasize bringing young investigators into the field. Specific events are directed specifically to the needs of graduate students. The funds will allow significant reduction in registration fees for students. |
0.915 |
1999 — 2001 | Arnold, Arthur P | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Determinants of Brain Sexual Differentiation @ University of California Los Angeles DESCRIPTION (applicant's abstract): The long term goal of the proposed studies is to understand the molecular signals that initiate sexually dimorphic development of the brain, and lead to sex differences in behavior. A great deal of experimental evidence indicates that one of these signals is testosterone, secreted by the testes before or after birth, which acts directly or indirectly on the brain of males to cause masculine patterns of neural development. However, some sex differences in the brain are not induced by gonadal steroids, and the proposed studies test an alternative hypothesis, that genes on the sex chromosomes are differentially expressed in male and female brain and lead, via non- hormonal mechanisms, to sex differences in neural development and behavior. To analyze this hypothesis, we will measure various parameters of brain structure and function, and of behavior, in male and female mice of selected genotypes that carry different numbers of X and Y chromosomes, or different portion of the sex chromosomes in varying numbers. The parameters to be measured are known sexual dimorphisms in brain structure and function and behavior. The proposed studies will determine if any genes on the Y or X chromosome contribute to sex differences in neural and behavioral development, and will narrow down the location of these genes to specific regions of the sex chromosomes. The proposed research will contribute significantly to an understanding of the principles of sexual differentiation of the brain. At issue are the molecular mechanisms by which male and female brains differ, which is highly relevant to biological basis of abnormalities of sexual differentiation, and to the explanation of sex differences in psychiatric and neural disease (e.g., Alzheimer's Disease and Multiple Sclerosis). |
0.936 |
2001 — 2005 | Arnold, Arthur P | T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Neuroendocrinology of Reproduction @ University of California Los Angeles DESCRIPTION (provided by applicant): This proposal seeks renewal of UCLA's pre- and post-doctoral Training Program in Neuroendocrinology of Reproduction, now in its 20th year. The Program is broad in the sense that it unites faculty with diverse expertise in a cooperative educational enterprise. It is focused in the sense that all faculty and trainees share in the pursuit of understanding the complex interactions of hormonal and neural systems in the control of reproduction. The training faculty are members of the Laboratory of Neuroendocrinology (LNE), a research unit of the Brain Research Institute. The faculty are twelve tenured or tenure-track faculty members representing eight departments of the UCLA School of Medicine and College of Letters and Science. All faculty are primarily or exclusively involved in research, but two are also physicians and thus bring a clinical perspective to the research of the group. A dominant characteristic of the LNE is active collaboration and interaction among the twelve independent research laboratories, at both the faculty and trainee levels, which considerably enriches the educational milieu for trainees. Trainees have free access to laboratories of all LNE faculty and to other laboratories of a world-class biomedical research center. Pre- doctoral trainees must be admitted to one of four Ph.D. programs (Neuroscience, Physiology, Neurobiology, or Human Genetics). Post-doctoral candidates apply directly to research mentors. The Training Program provides for weekly brown bag seminars, numerous didactic graduate courses and seminars in reproductive neuroendocrinology, the Distintzuished Visiting Scientist Program, and instruction in ethical conduct of science and career skills. Research opportunities available in the twelve laboratories include all levels of analysis (molecular and cellular to systems/behavioral and evolutionary), and involve numerous areas such as sex determination and sexual differentiation, hormonal regulation of neural function, gender differences in disease, cellular and molecular analysis of neural development, neural regulation of gonadal and adrenal function, glial neurobiology, stress, aging, neuroendocrine immunology, growth factors and cytokines, and genetic approaches. |
0.936 |
2003 — 2006 | Arnold, Arthur P | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex Chromosome Effects On Neural Development @ University of California Los Angeles DESCRIPTION (provided by applicant): The proposed studies have two long-term goals: (1) to understand the molecular signals that initiate sexually dimorphic development of the brain, and lead to sex differences in behavior and (2) to understand the effects of Y chromosome action on the brain. The proposal seeks to determine when and where Y chromosome genes are expressed in brain, and how they act. The sites and times of neural expression of Y chromosome genes will be determined. To establish correlations between Y chromosome expression in brain and the Y gene effects on behavior, Y chromosome gene expression in the brain will be compared in several dyadic comparisons of mouse strains that differ only in their Y chromosome and show differences in behavior attributed to the action of Y chromosome genes. These studies will identify candidate Y genes that are responsible for the Y-induced differences in behavior. The role of these candidate genes will be tested by measuring the reproductive and aggressive behavior of mouse strains that differ in level of expression of only a single Y gene. The reciprocal influence of Y genes and gonadal androgens will be tested by measuring the interaction of androgens and Y genes on behavior. The proposed research will contribute significantly to an understanding of the principles of sexual differentiation of the brain. At issue are the molecular mechanisms by which male and female brains differ, which is relevant to the biological basis of abnormalities of sexual differentiation, and to the explanation of sex differences in neurological and psychiatric disease (e.g., Alzheimer's Disease and Multiple Sclerosis). The proposed studies will also help explain genetic effects of sex chromosome aneuploidy (Klinefelter Syndrome 47,XXY, and 47,XYY) on behavior and will shed light on the forces that control reproductive behavior, aggressive behavior and hyperaggression. |
0.936 |
2003 — 2006 | Arnold, Arthur P | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex Differences in Dopamine Systems @ University of California Los Angeles DESCRIPTION (provided by applicant): The proposal has the long term goal of determining the factors that cause sex differences in structure, function, and susceptibility to disease in mesencephalic dopamine systems. The studies will investigate the cellular and molecular mechanisms by which sex chromosome genes induce sex differences in phenotype of dopaminergic neurons in vivo and in vitro. Studies will determine whether the sex chromosome effect is due to genes on the X or Y chromosomes; whether steroid hormones of the Sry gene participate in the induction of sex differences; when during development the sex chromosome effect occurs; whether the sex chromosome effect is direct or indirect on dopamine neurons; the cellular mechanisms of the sex chromosome effect; and whether the sex chromosomes contribute to sex differences in the development and adult structure of the nigrostriatal dopamine system in vivo. The proposed studies will contribute to an understanding of the principles of sexual differentiation of the brain. At issue are the molecular mechanisms by which male and female brains differ, which is relevant to the biological basis of abnormalities of sexual differentiation, and to the explanation of sex differences in neurological and psychiatric disease, not only of those that affect dopamine systems (e.g., Parkinson's Disease, Tardive Dyskinesia, Tourette's Syndrome, schizophrenia), but other sexually dimorphic diseases as well. (e.g., Multiple Sclerosis). Understanding sex differences in brain function will help develop sex-specific strategies for treatment of brain diseases. |
0.936 |
2006 — 2015 | Arnold, Arthur P | T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Neuroendocrinology, Sex Differences, and Reproduction @ University of California Los Angeles DESCRIPTION (provided by applicant): The goal of the UCLA Training Program in Neuroendocrinology, Sex Differences, and Reproduction is to educate pre- and postdoctoral scholars in research, including the ethical conduct of research, to prepare them for active careers in scientific research and/or teaching. The Training Program unites faculty with diverse expertise in a cooperative educational enterprise to provide a rich educational milieu for trainees. The faculty are outstanding scientists in the fields of genetics, molecular and cell biology, endocrinology, physiology, and behavioral science. The training faculty members of the Laboratory of Neuroendocrinology (LNE), a research unit of the Brain Research Institute, are members of 11 UCLA departments. All faculty are primarily or exclusively involved in research, but four are also physicians and thus bring a clinical perspective to the research of the group. A dominant characteristic of the LNE is active collaboration and interaction among the 15 independent research laboratories, at both the faculty and trainee levels, which considerably enriches the educational milieu for trainees. Trainees have free access to laboratories of all LNE faculty and to other laboratories of a world-class biomedical research center. This proposal requests funds to support 6 predoctoral and 3 postdoctoral scholars per year. Predoctoral students will be appointed for a period up to four years, and postdoctoral trainees for two years. Pre-doctoral trainees must be admitted to one of 7 Ph.D. programs. Postdoctoral candidates apply directly to research mentors. The Training Program provides for weekly brown bag seminars, numerous didactic graduate courses and seminars, the Charles Sawyer Distinguished Lectureship, instruction in ethical conduct of science and career skills, and for intensive mentoring of minority undergraduate students. The target fields of research include study of how the brain and gonads communicate with each other to control reproduction, how hormones affect the ability of the brain to respond to disease, how hormones and sex chromosome genes produce sex differences in the brain and other organs that influences their basic function and susceptibility to disease. The training program will help educate the next generation of scientists who will perform research to provide information that influences how physicians conceptualize and treat specific diseases, and how they treat diseases differently in men and women. PUBLIC HEALTH RELEVANCE: The proposed program will educate trainees to perform scientific research to understand the effects of hormones on the brain, sex differences in the function and diseases of the brain and other organs, and factors that control the ability to reproduce. This research will provide information physiological systems that are influenced by disease, or are protected from disease in one sex. This information will be helpful in developing novel therapies to reduce suffering from diseases of the brain and other organs, including those affecting the ability to reproduce. |
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2009 — 2013 | Arnold, Arthur P | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex Chromosome Effects On Neural Developement @ University of California Los Angeles Description (provided by applicant): Men and women differ in their behavior and susceptibility to disease. This project aims to understand the biological origins of sex differences in the brain and behavior, in health and disease. The novel mouse model, the four core genotypes (FCG), offers significant advantages for discriminating among several classes of biological factors that lead to sex differences in the brain, including organizational and activational effects of gonadal hormones, and direct effects of X and Y genes that are present in different numbers in the XX and XY genome. We propose to use the FCG model to investigate further sex differences in nociception and analgesia and in stress- induced changes in gastrointestinal motor function. A major goal is to develop a better understanding of direct actions of sex chromosome genes that lead to sex differences. We will investigate whether direct sex chromosome effects cause sex differences in stress-induced analgesia, in the effectiveness of kappa opioid analgesic drugs and their modulation by glutaminergic systems, in the effects of neuropathic nociception, and in effects of morphine. We will also investigate the sites and mechanisms by which sex chromosome genes lead to sex differences in neurovisceral changes underlying colonic motor responses induced by stress. The interaction of sex chromosome effects and gonadal hormone effects will be studied. We propose to identify X and Y genes that are directly responsible for the sex differences in these systems. The results will shed light on fundamental sex differences in nociception, stress, and neurovisceral responses to stress, leading to great understanding of sex-specific factors that ameliorate or exacerbate disease. |
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2010 — 2014 | Arnold, Arthur P Chen, Xuqi Reue, Karen (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex Differences in Obesity and Metabolic Disease @ University of California Los Angeles DESCRIPTION (provided by applicant): Men and women show different incidence and patterns of obesity, which is a major risk factor for diabetes, cardiovascular disease, and other metabolic and reproductive diseases. This project aims to understand the biological origins of these sex differences. We will use the novel mouse model, the four core genotypes (FCG), which includes mice with testes that have XX or XY sex chromosomes, and mice with ovaries that also have either XX or XY sex chromosomes. Thus, the FCG model offers significant advantages for discriminating among several classes of biological factors that lead to sex differences, including organizational and activational effects of gonadal hormones, and direct effects of X and Y genes that create an inherent sex bias in the function of XX and XY cells. We propose to use the FCG model to tease apart the effects of sex hormones (testicular or ovarian secretions) vs. sex chromosomes (XX vs. XY genotype) on energy balance, adipose tissue function, glucose and lipid homeostasis, and other aspects of metabolism. Physiological variables will be measured during manipulations of gonadal hormonal levels after gonadectomy and hormone replacement. The X-linked genes that cause sex chromosome effects on obesity will be identified by linkage studies, gene expression, and analysis of transgenic mice. The results will shed light on fundamental sex differences in obesity and metabolic disease, leading to greater understanding of sex-specific factors that ameliorate or exacerbate disease. |
0.936 |
2014 | Arnold, Arthur P Eghbali, Mansoureh |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Sex Differences in Myocardial Ischemia/Reperfusion Injury @ University of California Los Angeles DESCRIPTION (provided by applicant): Among all cardiovascular-related diseases, coronary artery disease still remains the leading cause of death in western countries. The incidence and progression of heart disease is markedly different in males and females, indicating that sex-biased factors can protect from disease. The long term objectives of this project are to identify processes, regulated by sex chromosomes and gonadal hormones, that affect cardiovascular disease, to improve the understanding of endogenous mechanisms of disease, and to identify sex-biased protective factors that may become targets for therapies. The project utilizes novel mouse models, which have already provided new evidence for striking differences in the response of XX and XY mice to myocardial ischemia/reperfusion injury, independent of the gonadal sex of the mice. These novel models vary the number or type of sex chromosomes in mice that have the same type of gonad, and thus allow the first understanding of the differential effects of XX vs. XY chromosomes. XX mice show dramatically greater susceptibility to ischemia/reperfusion injury, relative to XY mice, and lower post-ischemic heart contractile function. The XX vs. XY difference is attributable to the number of X chromosomes, not the presence/absence of the Y chromosome. Thus, the X chromosome harbors factors that strongly influence ischemia/reperfusion injury in a dose-dependent and sexually biased manner. Aim 1 is to investigate the physiological and molecular mechanisms that account for the XX vs. XY difference using these mouse models by measuring heart functional recovery and infarct size, mitochondrial function, superoxide production, and protective signal transduction pathways. Aim 2 is to first identify a list of candidate X gene(s) responsible for the XX vs. XY difference, and then to test the role of specific candidate genes by manipulating their expression in vivo. . Response to ischemia/reperfusion injury will be measured in mice with different doses of specific candidate X genes. Aim 3 is to manipulate the levels of adult gonadal hormones and type of gonad to understand how estrogens and androgens act on XX and XY mice to cause protection from ischemia/reperfusion injury. Response to ischemic insult will be measured as a function of hormonal level, sex chromosome complement and age. Discriminating the hormonal vs. chromosomal consequences of differences between females and males will provide an essential foundation for understanding factors that protect from ischemia/reperfusion injury, with an eye toward harnessing the protective factors to develop novel therapies. |
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2014 — 2018 | Arnold, Arthur P Jentsch, J. David Vilain, Eric J. (co-PI) [⬀] White, Stephanie Ann (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Mechanisms in Klinefelter Syndrome-Related Behaviors @ University of California Los Angeles DESCRIPTION (provided by applicant): Klinefelter Syndrome (KS) is a common chromosomal abnormality of males who have two X chromosomes XXY, rather than one, XY. XXY males experience a variety of congenital developmental problems, including infertility, lower levels of androgens, increased risk for obesity and metabolic disease, increased risk for autoimmune diseases, and cognitive features including alterations in executive function and delayed language development. The long-term objectives of this project are to identify X chromosome genes that cause behavioral features of Klinefelter Syndrome, using novel mouse models. An overarching question is to separate the direct effects of X chromosome genes that cause Klinefelter Syndrome traits, from those caused by lower testosterone levels in XXY individuals. A novel mouse model produces XXY, XY, and XX mice that have either testes or ovaries, so that sex chromosomal effects can be identified that do not require testicular secretions, or occur when testicular secretions do not explain differences. Mice will be compared in a series of Klinefelter Syndrome-relevant behavioral measurements that assess executive functions, development of vocalizations, and partner preference. The expression levels of six specific X chromosome genes, which are the major candidates for causing the features of Klinefelter Syndrome, will be directly manipulated to assess which is/are likely the causal genes in the mouse model. |
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2016 | Arnold, Arthur P Reue, Karen [⬀] |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
X Chromosome Dosage and Metabolic Disease @ University of California Los Angeles Abstract Men and women show different incidence and patterns of obesity, which is a major risk factor for diabetes, cardiovascular disease, and other metabolic and reproductive diseases. In mouse models, mice with two X chromosomes have much greater adiposity and dysregulation of lipid metabolism compared with mice with one X chromosome. Thus, the X chromosome encodes factors that contribute to sex differences in metabolism and adiposity. This project aims to understand the metabolic impact of one class of X chromosome genes that are represented differently in nearly all XX and XY cells. These are X genes that escape X inactivation ubiquitously and are expressed from both X chromosomes in XX cells, at a higher level than from the single X chromosome in XY cells. The difference in X gene dosage is hypothesized to give rise to XX vs. XY differences in metabolic disease. Preliminary evidence indicates that one gene escaping X inactivation, histone demethylase Kdm5c, accounts in part for large differences in adiposity and lipid metabolism of mice with one vs. two X chromosomes. The project will investigate the physiological and genomic effects of one vs. two copies of Kdm5c. We will determine the mechanism by which Kdm5c dosage influences adiposity by measuring energy balance, circadian regulation, and related metabolic parameters. We will determine the tissue site(s) of Kdm5c action that account for its effects on adiposity using anatomical and genetic Cre recombinase-mediated strategies. To address the molecular mechanism of Kdm5c dosage effects on adiposity, we will identify which genes are targets of KDM5C histone demethylase activity, resulting in changes in chromatin structure and gene expression. This will inform us about specific gene pathways that are altered by Kdm5c dosage that result in changes in adiposity and metabolism. Because the closely similar Y chromosome paralog Kdm5d appears not to have the same metabolic effects as X-linked Kdm5c, the comparison of the physiological effects, chromatin modifications, and gene expression modulated by Kdm5c and Kdm5d will help to recognize the gene pathways that are regulated by Kdm5c and relevant to metabolism. The results will shed light on fundamental sex differences in obesity and metabolic disease, leading to greater understanding of factors that ameliorate or exacerbate disease. |
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2016 — 2019 | Arnold, Arthur P Eghbali, Mansoureh |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epigenetic Regulation of Myocardial Ischemia/Reperfusion Injury by X Chromosome @ University of California Los Angeles ? DESCRIPTION (provided by applicant): Among all cardiovascular-related diseases, coronary artery disease remains the leading cause of death in western countries. The incidence and progression of heart disease is different in males and females, indicating that some protective factors are enhanced in one sex. The long term objectives of this project are to identify cellular and genetic mechanisms, regulated by sex chromosomes and gonadal hormones that affect cardiovascular disease, to improve the understanding of endogenous mechanisms of disease, and to identify sex-biased protective factors that may become targets for therapies. Previous research from our labs indicated that the number of X chromosomes causes striking differences in the response of XX and XY mice to myocardial ischemia/reperfusion injury, independent of the gonadal sex of the mice. XX mice show dramatically greater susceptibility to ischemia/reperfusion (I/R) injury, relative to XY mice, and lower post-ischemic heart contractile function. The XX vs. XY difference is attributable to the number of X chromosomes, not the presence/absence of the Y chromosome. Kdm6a is an X chromosome gene that escapes inactivation and is expressed higher in XX than XY cells, and two copies of this gene (as occurs in XX cells) cause greater I/R injury than one copy (as occurs in XY cells). The central hypothesis is that Kdm6a contributes to X chromosome dependent me /R injury via epigenetic regulation. Moreover, because estradiol is a female-enhanced factor that protects from I/R injury, one hypothesis is that estradiol regulates gene targets of KDM6A. Aim 1 will test whether KDM6A is responsible for the XX vs. XY difference in I/R injury by measuring infarct size and heart functional recovery in mice with different copy numbers of Kdm6a (deleting one copy of Kdm6a from XX mice, and adding Kdm6a to XO mice). Aim 2 will discover direct targets of histone demethylase KDM6A, and measure the changes in expression of genes regulated by KDM6A dosage. These studies will define a short list of genes downstream of KDM6A that can be tested to determine if they mediate KDM6A's effects on me /R injury. Aim 3 will compare the effects of two female-specific factors, estradiol secreted from the ovary, and the presence of a second X chromosome, to establish how each factor influences the effect of the other. Genes regulated by KDM6A will be tested to determine if they are also regulated by estradiol. These studies are intended to provide a more sophisticated mechanistic understanding of the differences in I/R injury in females and males, with an eye towards discovering novel protective mechanisms that could become targets for therapy in both sexes. |
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2017 — 2018 | Arnold, Arthur P Mackenzie-Graham, Allan James |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Discriminating Sex Chromosome and Hormonal Effects On Brain Sexual Dimorphisms @ University of California Los Angeles Project Summary / Abstract Men and women show different incidence and patterns of neurological and psychiatric diseases, indicating that one sex may possess higher levels of factors that protect from disease, or lower levels of factors that exacerbate disease. The long-term goal of the project is to determine which brain regions are influenced by sex-biasing factors such as the genes encoded by the sex chromosomes and the level of gonadal hormones in adulthood. Because these types of sex-biased protection are mediated by different molecular mechanisms, discriminating the sites of action of each factor is the first step towards understanding how sex-biased protection operates. The proposed research involves whole-brain magnetic resonance imaging to measure the size of every brain region, under conditions in which specific sex-biasing factors can be rigorously manipulated to observe their individual effects. The brains of sex chromosome aneuploid and wild-type (XO, XX, XY and XXY) will be compared when mice have or do not have their gonads. The experimental design will determine which sex differences in volumes of brain regions are influenced by the number of X chromosomes, and by the presence / absence of the Y chromosome, and by the levels of testicular and ovarian secretions in adulthood. The results will establish the brain regions and localized functions that are influenced by different sex-biasing mechanisms. The outcome will alter conceptual frameworks for investigating protective mechanisms in brain regions affected by neurological and psychiatric disease. |
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2018 | Arnold, Arthur P Dwinell, Melinda R Geurts, Aron M (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Sry Transgenic Rats For Investigation of Xx Vs. Xy Differences in Phenotypes @ University of California Los Angeles Project Summary Most diseases occur differently in males and females, indicating that one sex is protected by factors that are inherently different in the two sexes. Understanding the mechanisms of protection involves isolating different molecular pathways causing greater or less protection. Sex chromosomes (XX vs. XY) are one major source of sex bias within any type of cell, but this category has been difficult to discriminate from gonadal hormone effects that often co-vary with sex chromosome complement. To isolate and study sex chromosome effects, it is necessary to make experimental models with XX and XY animals with the same type of gonad. No such models exist in rats. Rats are superior models for many diseases and physiological processes. The proposal is to genetically modify rats to produce XX and XY rats with testes, and XX and XY rats with ovaries, to be studied in many different rat models of disease, relevant to nearly any NIH institute. The testis- determining gene Sry, present on the Y chromosome, will be inserted as a transgene onto an autosome, so that XX(Sry-tg+) gonadal male rats can be compared with XY gonadal male rats. Then, Sry will be knocked out from the Y chromosome, producing XY rats with ovaries, gonadal females, which can be compared with XX gonadal females to detect the differential effects of XX vs. XY sex chromosomes. The basic gonadal and body development of these rats will be studied to validate their use in numerous rat models of disease, including brain and behavioral phenotypes, cardiovascular and pulmonary diseases, etc. The successful models will be deposited in the Rat Resources & Research Center and made widely available to other investigators. |
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2020 — 2021 | Arnold, Arthur P | R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Organization For the Study of Sex Differences Annual Meetings @ University of California Los Angeles SUMMARY Support is requested for the 14th through 18th Annual Meetings of the Organization for the Study of Sex Differences (OSSD). The 14th Annual Meeting of the OSSD will be held May 4-7, 2020 at the Marriott Hotel in Marina del Rey, California, near the Los Angeles International Airport. Subsequent meetings are planned annually beginning with San Antonio TX in 2021, and Calgary, Alberta, Canada in 2022. The mission of the OSSD is to enhance knowledge of the biological basis of sex/gender differences and the contribution of sex as a biological variable to health and disease by facilitating interdisciplinary communication and collaboration among scientists and clinicians from diverse scientific and professional backgrounds. The primary goal of the OSSD annual meeting is to provide a forum for scientists to explore aspects of sex differences research at the genetic, molecular, cellular, organ, and systems levels in humans and model systems. The annual meeting consists of one workshop, major Keynote and Capstone lectures, 16-20 parallel scientific symposia including a New Investigators Symposium, and two poster sessions highlighting the work of new investigators and trainees. The title for the OSSD 2020 meeting is ?Sex Differences Across the Lifespan?, with a specific focus on aging and age-related diseases. Session topics are selected in a highly competitive process, with emphasis on scientific excellence and diversity of topics. The meeting typically serves 250 participants. A strong focus on trainee education includes several programs aimed specifically at didactic activities and career development. Underrepresented minority scientists are well represented among meeting leaders, speakers, and attendees. Specific programs are organized to foster involvement of underrepresented minority individuals at all levels. Funds are requested to support registration fees for invited distinguished speakers, conference / travel support for junior investigators and trainees, attendance by minority undergraduate students, and expenses related to room rental and associated technical support, and poster board rentals. The annual meeting program, including speaker and poster abstracts will be freely available on the OSSD website. |
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2020 — 2021 | Arnold, Arthur P | R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Organization For the Study of Sex Differences Annual Meeting @ University of California Los Angeles SUMMARY Support is requested for the 14th through 18th Annual Meetings of the Organization for the Study of Sex Differences (OSSD). The 14th Annual Meeting of the OSSD will be held May 4-7, 2020 at the Marriott Hotel in Marina del Rey, California, near the Los Angeles International Airport. Subsequent meetings are planned annually beginning with San Antonio TX in 2021, and Calgary, Alberta, Canada in 2022. The mission of the OSSD is to enhance knowledge of the biological basis of sex/gender differences and the contribution of sex as a biological variable to health and disease by facilitating interdisciplinary communication and collaboration among scientists and clinicians from diverse scientific and professional backgrounds. The primary goal of the OSSD annual meeting is to provide a forum for scientists to explore aspects of sex differences research at the genetic, molecular, cellular, organ, and systems levels in humans and model systems. The annual meeting consists of one workshop, major Keynote and Capstone lectures, 16-20 parallel scientific symposia including a New Investigators Symposium, and two poster sessions highlighting the work of new investigators and trainees. The title for the OSSD 2020 meeting is ?Sex Differences Across the Lifespan?, with a specific focus on aging and age-related diseases. Session topics are selected in a highly competitive process, with emphasis on scientific excellence and diversity of topics. The meeting typically serves 250 participants. A strong focus on trainee education includes several programs aim specifically at didactic activities and career development. Underrepresented minority scientists are well represented among meeting leaders, speakers, and attendees. Specific programs are organized to foster involvement of underrepresented minority individuals at all levels. Funds are requested to support registration fees for invited distinguished speakers, conference / travel support for junior investigators and trainees, attendance by minority undergraduate students, and expenses related to room rental and associated technical support, and poster board rentals. The annual meeting program, including speaker and poster abstracts will be freely available on the OSSD website. |
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2020 — 2021 | Arnold, Arthur P Lerch, Jason P. Mackenzie-Graham, Allan James |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
@ University of California Los Angeles Abstract Many neurobehavioral diseases affect females and males differently, and emerge at different stages of life, leading to the conclusion that one sex is protected from diseases by inherent sex factors, such as gonadal hormones and sex chromosomes. The sites and timing of these effects on brain development are unknown. The method of high-throughput high-precision whole-brain MRI imaging has the power to detect such changes with great sensitivity, in both animal models and humans. This project will exploit these powerful methods to separate gonadal hormonal and sex chromosome effects in the mouse model ?Sex Chromosome Trisomy? (SCT), at 9 different ages of development, to discover where and when these factors cause sex differences in brain development (Aim 1). The SCT model compares mice with different numbers and types of sex chromosomes (XX, XY, XXY, XYY), each genotype present in gonadal males or females. Then, a novel pipeline of analysis will compare mouse and human brain development at many stages and in informative groups (differing by age, sex, hormonal status, and sex chromosome complement) to determine which changes in mouse brain are also found in humans, in specific brain regions related to different diseases (Aim 2). The analysis will point to changes in mouse brain that model human brain development. These studies will also pinpoint new sex-biasing effects of hormones and sex chromosomes at localized brain regions at specific developmental stages in mice, leading to further investigation of cellular and molecular changes caused by sex at those sites (Aim 3). Cellular effects (cell size, number, density of defined cell populations) of sex-biasing factors will be measured using CLARITY (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue- hYdrogel). Gene pathways responding to hormonal and sex chromosome effects in individual cell types in specific brain regions will be measured using single cell RNA-seq. These studies, combining high- resolution neuroimaging, CLARITY, and single cell sequencing, will provide a foundation of concepts about where in the brain, and when during development, specific cell populations respond to sex factors, as a prelude for hypothesizing which sex differences underlie the protective effects of sex- biased factors in cells. |
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2021 | Arnold, Arthur P Dwinell, Melinda R Geurts, Aron M (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Transformative Rat Models to Study Sex Differences in Disease @ University of California Los Angeles Project Summary The long-term objectives are to develop and validate rat models of disease that allow investigators to measure the differential effects of XX and XY sex chromosomes that protect from or exacerbate disease. Most human diseases occur differently in males and females, indicating that one sex is protected or vulnerable because of factors that are inherently different in the two sexes. Understanding the mechanisms of protection or vulnerability involves isolating different molecular pathways causing greater or less protection. Sex chromosomes (XX vs. XY) are one major source of sex bias within any type of cell, but this category has been difficult to discriminate from gonadal hormone effects that often co-vary with sex chromosome complement. To isolate and study sex chromosome effects, it is necessary to make experimental models comparing XX and XY animals with the same type of gonad. Such models have not been available to investigators who study rats, but have just become available. The modified rats have two genetic mutations, to introduce the testis-determining gene Sry onto a non-sex-chromosome, and to knock Sry out on the Y chromosome. These modifications produce XY and XX rats with ovaries, and XX and XY rats with testes. The proposal is to study the newly developed genetically modified rat lines, to establish the nature of genetic sequence in and near the two genetic modifications, and to determine how the modifications change the development of ovaries and testes. Rats bearing these modifications will be compared to normal rats, to measure: physiology of reproduction, sexual development of the brain, cardiac function, systemic and pulmonary hypertension, and hypertension- related cognitive function. Rats offer significant advantages as models of human physiology and disease, because of their large size, the large literature concerning basic physiology and sex differences in rats, their superior cognitive ability, and suitability of rats to research on specific diseases. The successful rat models will be deposited in the Rat Resources & Research Center and made widely available to other investigators. |
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