Center for Gender, Hormones and Health
LIST OF INVESTIGATORS AND PROJECTS CURRENTLY ACCEPTING TRAINEES.
Anat Biegon PhD, Neurology and Radiology
http://neuro.stonybrookmedicine.edu/about/faculty/biegon
1. Effect of gender and hormonal status on outcome of traumatic brain injury
Using retrospective data analysis as well as prospective data collection, we are examining the distribution of
outcomes men and women who have sustained a traumatic brain injury. In the retrospective arm, outcome is
measured by the GOSE or modified Rankin scores and hormonal status is inferred from age; with age 50
considered the cutoff for menopause. In the prospective arm, actual sex steroids levels (testosterone, estradiol
and progesterone) will be measured in blood and neuropsychological outcome will be added to the GOSE.
2. Sex differences and sex steroid markers in Alzheimer’s disease: in vivo and postmortem studies.
Using immunohistochemistry, RT PCR and quantitative autoradiography, we are conducting a detailed analysis
of the regional and cellular distribution of sex-steroid related markers (aromatase, estrogen receptors androgen
receptors) and BDNF in postmortem samples form hippocampus and basal ganglia of subjects who died with
Alzheimer’s disease and non-demented controls. Non-invasive imaging studies with PET and MRI are used to
investigate sex differences and aromatase levels in subjects with mild cognitive impairment (MCI), Alzheimer’s
disease and health age matched controls.
3. Impact of brain regional estrogen synthesis on personality and cognitive abilities in men and women.
Regional estrogen synthesis capacity is examined using PET and the aromatase tracer [11C]vorozole in health
individuals in conjunction with tests of general intelligence, verbal memory and stable personality traits.
Specific tests for aggression are included in a study of steroid abusing men performed in collaboration with
investigators from Mount Sinai School of Medicine.
4. Impact of brain regional estrogen synthesis on obesity.
PET studies with the aromatase tracer [11C]vorozole are used the assess the relationship between estrogen
synthesis capacity in various brain regions and body mass index (BMI) in normal weight , overweight and
obese men and women. Personality traits relevant to impulsivity / self control are examined in the same
individuals. The goal is to evaluate regional aromatase uptake in the brain as a possible predictor of successful
long term weight maintenance after bariatric surgery.
Patricia Coyle MD Neurology
https://www.neuronext.org/patricia-coyle
Dr. Coyle is interested in the effects of gender and hormonal status on disease course in multiple sclerosis.
Studies include an examination of the effect of menopause on frequency of exacerbations and lesions
identified on MRI in relapsing remitting disease and an examination of the impact of gonadal steroid levels in
men and women on exacerbations and MRI.
Dr. Coyle is also principal investigator on several pharma - sponsored clinical trials in remitting relapsing as
well as primary and secondary progressive disease which include both men and women and will help identify
sex differences in experimental drug response. .
Daniel Klein PhD. Dept. Psychology
http://www.stonybrook.edu/commcms/psychology/faculty/faculty_bio_pages/dklein.html
Dr. Daniel Klein, Professor of Psychology, is working to identify early risk factors and precursors for later
depressive and anxiety disorders, as well as mediators and moderators of the paths between risk factors and
outcomes. He is following a cohort of children at 3-year intervals from preschool through adolescence, when
significant sex differences emerge and females experience a marked increase in depression and anxiety.
This is a multi-level, multi-method project that examines the effects of genes, child temperament, parenting and
parental psychopathology, neural and behavioral indices of children's processing of emotional stimuli,
stress and sex hormones, peer and romantic relationships, and life stress on the emergence of depressive and
anxiety symptoms. It provides an excellent opportunity to address questions regarding the development of
sex differences in depression and anxiety, such as whether there are sex differences in early risk factors that
interact with later events in adolescence, or whether the developmental trajectories of risk factors first begin to
diverge in early adolescence.
We can provide a variety of opportunities for post-doctoral fellows to work on this project and gain exposure to
a variety of substantive and methodological areas, as well as to participate in other collaborative projects being
conducted at Stony Brook and other universities.
Mary Kritzer PhD, Neurobiology
http://medicine.stonybrookmedicine.edu/neurobiology/faculty/Kritzer
In collaboration with the Sirotkin lab, we are developing novel adeno-associated virus (AAV) based tools for
selectively silencing intracellular hormone receptor signaling in specific regions and cells of the central nervous
system in adult rats. Our major focus is currently on the androgen receptor and investigations of the neural
bases for male vulnerability to executive dysfunction in Parkinson’s disease, schizophrenia and other
neurologic and neuropsychiatric disorders. In each of these conditions, cognitive symptoms include
perseveration, impulsivity and working memory deficits. These occur more often and more severely in males
but in both sexes executive dysfunction is resilient to and even exacerbated by the treatments that are most
commonly used to treat the parent disorders. This adds urgency to the problem of finding new approaches to
treating disease-related cognitive impairment. Accordingly, our goals are to define hormone impact in the CNS
and use this information to develop therapies that deliver benefits for brain and behavior while avoiding the
health risks associated with hormone augmentation and deprivation. This requires detailed knowledge of
hormone effects that are specifically and selectively levied upon the brain, and the precise identification of
downstream targets. However, available methods of experimental investigation, i.e., gonadectomy and
hormone replacement, naturally occurring and engineered gene mutations in rodent strains, administration of
hormone receptor agonists/antagonists and others are unable to differentiate hormone actions that are local to
specific brain regions from those that related to more widespread actions occurring elsewhere in the brain and
body. Our strategy is to use AAVs to direct targeted genome editing (CRISPR-Cas9) and gene silencing
(TALE-repressors) to develop well-tolerated, temporally controllable, long-term means of silencing hormone
receptor transcription in regions of interest in the adult rat brain. Our plan includes development of AAVs
engineered to allow both regional and cellular selectivity in silencing receptor transcription. By establishing
such new means for interrogating hormone action in the CNS, we will be well-positioned to address emerging
hypotheses about sex differences in cognitive function and in the cognitive dysfunction in PD and other
disorders. These new tools are being combined with genomic, proteomic and electrophysiological analyses at
single, identified cell levels and with in vivo assessments of brain chemistry (microdialysis, PET) and of
behavior to obtain an unprecedented molecular- to-systems level understanding of the contributions of gonadal
steroids to the executive centers of the adult male and female brain.
Maricedes Acosta-Martinez; Dept. of Physiology & Biophysics
http://pnb.informatics.stonybrook.edu/faculty/acosta.shtml
Basic Research:
My laboratory investigates the interplay between metabolism and reproductive physiology. Although the
mechanisms mediating the influence of metabolism and nutrition on fertility are currently unclear, the strong
association between metabolic disorders and infertility is undeniable. For example, women suffering from
anorectic disorders experience amenorrhea as a consequence of malnutrition-induced impairment of
luteinizing hormone (LH) release, and at the other extreme, obesity is also commonly co-morbid with menstrual
dysfunction and infertility. Many cases of infertility result from alterations in the regulation of gonadotropin
releasing hormone (GnRH) secretion by peripheral metabolic signals. The goal of my studies is to understand
how hypothalamic neurons integrate hormonal and metabolic signals to maximize reproductive and metabolic
fitness. Specifically, my laboratory seeks to elucidate the molecular mechanisms by which sex steroid
hormones and metabolic signals relay information about nutritional status to the GnRH network. Our research
has demonstrated that in the hypothalamus, molecules that function as cellular energy sensors regulating
feeding and metabolism also serve as mediators of steroid feedback actions on reproduction, including
pubertal development and gonadotropin release. These molecules ensure that metabolic and reproductive
fitness are integrated. Importantly, our work has shown that their function in specific neurons is sex-specific.
For example, GnRH and kisspeptin neurons are pivotal for the onset and maintenance of fertility, and their
activity is influenced by gonadal hormones and by metabolic cues. Using a combination of transgenic animal
models, neuroimaging and molecular biology techniques, my laboratory has demonstrated that PI3K signaling
in GnRH and kisspeptin neurons participates controlling gonadotropin release and neuropeptide gene
expression in a sexually dimorphic fashion. Ongoing studies in my lab include: 1) Investigating the impact of
metabolic stress on gonadotropin release in mice with impaired PI3K signaling in kisspeptin neurons, 2)
Testing the hypothesis that PI3K mediates estradiol effects on metabolism and reproduction, and 3)
Investigating whether estradiol regulation of autophagy, a PI3K-regulated cellular process, participates in the
control of metabolism and reproduction. Poor nutrition and obesity are linked to multiple hormonal and
reproductive disorders. For example, obesity is associated with earlier pubertal onset in girls which is in turn
associated with increased risk of breast cancer, cardiovascular disease, asthma, and type 2 diabetes. Obesity
also exacerbates the reproductive and metabolic abnormalities accompanying polycystic ovarian syndrome
(PCOS), the most common reproductive disorder among women of reproductive age. Thus, to alleviate the
health burden accompanying obesity, it is imperative to achieve a better understanding of the mechanisms
underlying the metabolic control of HPG axis function. Only then can we potentially devise therapies that
reduce the risk of metabolic-related disorders such as early puberty and PCOS.
Clinical/Translational Research:
Profiling of circulating exosome-miRNAs during pregnancy: potential biomarkers to monitor and
predict pregnancy-associated disorders like gestational diabetes.
The lack of reliable diagnostic tests for early detection of pregnancy-specific disorders such as gestational
diabetes and preeclampsia remains an unmet challenge in maternal/fetal medicine. The diagnosis of these
pregnancy complications occurs during or after the second trimester, when the pathology is well established
and the options to reverse or limit adverse outcomes are limited. Exosomes are bilipid membrane-boundnanovesicles released via exocytosis from virtually every tissue, including the placenta. They are excellent
candidates for translational biomarkers because their surface signals as well as cargo are dependent on their
cell of origin as well as on the physiological or pathophysiological state. Obesity before and during pregnancy
is a major risk factor for two of the most common medical risks in pregnancy: diabetes and hypertension. While
pregnancy is associated with a significant increase in plasma exosomes, to date no study has investigated the
differential expression of circulating pregnancy-associated exosomes and their content in healthy pregnancies
vs. those in high-risk pregnancies such as obese pregnant women. In collaboration with the Dept. of
Obstetrics, Gynecology and Reproductive Medicine, my laboratory is characterizing the expression profile of
circulating exosome-derived miRNAs from pregnant women with a normal BMI and obese pregnant women
with BMI > 30 kg/m2. By investigating circulating miRNA expression during pregnancy, our study focuses on a
specific molecular mechanism underlying differential gene expression during the evolution of pregnancyassociated diseases. Therefore, our studies have the potential to provide a new clinical strategy to identify
women at risk of developing diseases associated with maternal obesity.
Kenneth R. Shroyer, MD, PhD, Professor and Chair of Pathology
http://medicine.stonybrookmedicine.edu/pathology/faculty/shroyer
Current research in my lab is focused on both translational studies and basic mechanisms relating to novel
prognostic cancer biomarkers. We have identified over 2000 candidate biomarkers by MALDI-TOF Orbitrap
analysis in the Stony Brook Proteomics Core Lab facility and have discovered that high expression of keratin-17
(K17) predicts poor outcome in patients with cervical cancer, at both early and late stages of disease, more
accurately than either tumor staging or loss of p27(KIP1) as a negative prognostic marker.
We investigated the mechanistic basis for the biologic impact of K17 through loss- and gain-of-function
experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17
functions as an oncoprotein by regulating the subcellular localization and degradation of p27(KIP1). We found
that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization
signal (NLS), specific among keratins, where it bound p27(KIP1) during G1 phase of the cell cycle.
Subsequently, we were able to demonstrate that K17 mediates cancer cell-cycle progression and tumor
growth by promoting p27KIP1 nuclear export and degradation.
Ongoing areas of investigation in my laboratory include translational studies related to the targeting of nuclear
K17 as a biomarker for cervical cancer screening in low resource settings and also on furthering our knowledge
regarding how K17 serves as an oncofillament to drive progression of cancers of the cervical mucosa, breast,
and other anatomic sites.
The Department of Pathology at Stony Brook Medicine is well equipped to provide an optimal trailing
environment to prepare students to pursue research careers in cancer disparities research, encompassing a
focus on the most common causes of cancer mortality in women, including carcinomas of the female genital
tract and breast.
Styliani-Anna (Stella) E. Tsirka PhD. Dept. Pharmacological Science
http://www.pharm.stonybrook.edu/faculty/t/tsirka
Immune-competent microglia cells constantly survey the central nervous system and coordinate responses
to exaggerated neuronal stimulation or neuronal injury. It was shown recently that in the context of neuropathic
pain, the activated microglia direct a differential response and pain tolerance depending on whether the cells
derive from male or female mice. We are using naive and activated microglia to determine by RNAseq gene
expression differences between the two genders. We will confirm such potential differences and examine the
relevant genes in injury and disease models where a gender difference in responses has been noted, namely
in the experimental allergic encephalomyelitis model for multiple sclerosis, and in spinal cord injury.
In collaboration with Dr. Acosta-Martinez we will also examine the importance of estrogen regulation on
microglia and the response of microglia to estrogen or progesterone, as well as their role in neurosteroid
synthesis.