Pilot Project Program

Development of MUC4-targeted CAR-T cell therapy for Uterine Corpus Endometrial Carcinoma

Avik Chattopadhyay, Ph.D.
Uterine Corpus Endometrial Carcinoma (UCEC) represents a significant health concern in women, particularly as one of the most prevalent gynecological malignancies. Current therapeutic options for advanced and recurrent UCEC are limited, underscoring the urgent need for targeted therapies. We have identified MUC4, a membrane-associated mucin, as being significantly overexpressed in UCEC tumors and associated with poor prognosis and increased tumor aggressiveness. Our goal is to develop and optimize MUC4-specific CAR-T cells to target UCEC, assessing their anti-tumor efficacy and safety in vivo using UCEC xenograft models. The development of MUC4-targeted CAR-T cell therapy holds transformative potential by offering precise and effective immunotherapy against UCEC. By specifically targeting the tumor-associated antigen MUC4, this project aims to minimize off-tumor toxicity while enhancing therapeutic efficacy, paving the way for personalized and potentially curative treatment approaches in UCEC patients.

The sex-dependent role of anti-endothelin receptor A autoantibodies in systemic Lupus Erythematosus-associated cognitive and renal injury

Marice McCrorey, Ph.D. student.
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by the production of autoantibodies and chronic inflammation. SLE predominantly affects women with a high prevalence in minorities. Interestingly, the incidences of vascular complications affecting the central nervous system (CNS) and kidney are markedly increased in SLE patients compared to healthy patients. Additionally, SLE patients suffer from multiple neuropsychiatric which are classified as Neuropsychiatric SLE (NPSLE). However, the current understanding of how autoantibodies in SLE may contribute to inflammation and end-organ damage remains poorly understood. The identification of elevated autoantibodies against endothelin receptor A (ETAR), a proinflammatory and vasoconstrictive signaling molecule that strongly correlates with the presence of SLE leads us to explore its role in the progression of renal injury and cognitive decline in SLE. This project aims to elucidate the mechanism through which anti-ETAR antibodies promote inflammatory environments in the renal and cerebral vasculature and identify whether endothelin receptor A antagonism may prove beneficial to the renal and cerebral health in SLE patients.

Examining the sex-dependent mitochondrial consequences of Cyp2e1 deletion in mice

Kristina Stayer, Ph.D. student
Human liver diseases are sex-dependent. Women experience a faster progression and greater severity of alcoholic liver disease (ALD), whereas men have faster progression and greater severity of metabolic dysfunction associated liver disease (MASLD). An important liver enzyme that is associated with both diseases is cytochrome P450 2E1 (CYP2E1). CYP2E1 is an evolutionarily conserved enzyme known for metabolizing many substances such as ethanol and fatty acids. Recently, in our CYP2E1-deleted (KO) mouse model, we have found that liver mitochondria in the female KOs at baseline appear to be compromised. Additionally, when comparing gene expression of the livers of the KO and wild-type CYP2E1-expressing (WT) animals, the females have far more differentially expressed genes (~7000 genes in females versus ~500 in males). This data taken together indicate that Cyp2e1 deletion in the female liver may be more consequential. Unfortunately, most studies in the liver have been limited to the use of male models. This is a problem, as the liver is a sexually dimorphic organ thus extrapolating the results of male studies to females is problematic. The goal of this study is to better understand the importance of Cyp2e1 in female livers by characterizing the effect Cyp2e1 KO has on mitochondrial morphology and energetics.

Sex/gender related differences in reasons for using cannabis and perceived problem severity, Kathryn Gex, Ph.D.- Cannabis use is increasing across the lifespan, especially among women. Given that women progress more rapidly from first use to use disorder onset (telescoping), understanding sex/gender differences across the lifespan in reasons for use and the perceived severity of cannabis consequences is critical for prevention and intervention efforts. Improved understanding of these phenomena will enhance the efficacy of existing prevention/early intervention approaches for adolescents and young adults, as well as inform the development of needed education programs sought by mid-life and older adults. Thus, the goal of this study is to begin to address important gaps in the literature regarding: 1) reasons for cannabis use among mid-life and older adult men and women and how these reasons are associated with use and problems at different life stages, and 2) perceived severity of cannabis consequences and how this may relate to continued cannabis use.

Examining sex differences in empathy in autistic children, Rosmary Ros-Demarize, Ph.D.- This study will examine cognitive and emotional empathy in a sample of autistic children and adolescents (ages 8-17) using approaches to fairly weight research participants by sex. The sample will include male and female autistic children with and without comorbid oppositional defiant or conduct disorder(ODD/CD) diagnoses. This study uses a novel approach in that it connects reported empathy to reported aggressive and prosocial behaviors, capturing both internal states and related behaviors. Further, the current study will make use of the national SPARK cohort and the SPARK Research Match program, which allows researchers to combine already collected data (sociodemographic, CBCL, Vineland) with study specific data (empathy measures) to reduce participant burden and strengthen the feasibility of the proposed project.

Accelerated intermittent theta-burst stimulation for postpartum depression: Toward reducing treatment burden to enhance outcomes for new mothers, Anna Ehrhardt, M.D.: Postpartum depression (PPD) is the most common complication of childbirth, affecting 20% of new mothers. PPD can adversely affect maternal-infant bonding, breastfeeding, and child development. Current therapies for PPD have side effects of particular concern for new mothers including the potential for antidepressants to cross over into breast milk or ECT to induce memory impairment. This renders rTMS, a treatment with relatively fewer side effects, a potentially more attractive option. A conventional, FDA-approved TMS treatment course runs for 4-6 weeks with 30 daily appointments, posing a burden to busy new mothers. Accelerated (multiple treatments per day) theta burst rTMS significantly shortens total treatment time and has similar efficacy to conventional rTMS. With this pilot study, we look to determine the feasibility, tolerability, acceptability, and credibility of accelerated rTMS for treating PPD. We will also be estimating preliminary effect size to do a power analysis for a future randomized, sham-controlled trial of accelerated rTMS for treatment of PPD as well as exploring barriers to treatment for new mothers.

Pharmacotherapy for adolescent alcohol use: Investigating sex differences in cue-reactivity and neuroinflammation, ReJoyce Green, Ph.D.: Sex differences in alcohol use and alcohol-related consequences may substantially impact treatment outcomes. The pilot project utilized data from a recently completed adolescent pharmacotherapy trial examining neural response to a novel pharmacotherapy, N-acetylcysteine (NAC), for adolescent alcohol use. The project examined two novel treatment outcomes, reactivity to alcohol cues and markers of neuroinflammation, to test whether females respond more favorably to NAC. Results from the pilot project addressed a critical gap in the literature of how sex may alter response to pharmacotherapy for alcohol use among adolescents.

Sex-associated difference in mitochondrial stress response following traumatic brain injury, Onder Albayram, Ph.D.: Traumatic brain injury (TBI) is a leading cause of disability and mortality, resulting in over 3 million TBI related hospital visits in the US and 80,000 deaths each year.  An increasing number of studies demonstrate significant sex differences in response to TBI, with females exhibiting more resistance to secondary injuries and better outcomes in comparison to their male counterparts. Dysfunctional mitochondrial stress response/mitophagy is a major driver of the secondary deleterious cascades following brain injury. Accumulating evidence suggests that propensity of mitophagy may vary between males and females, particularly in conditions of cellular stress such as TBI. However, it still unknown how sex differences in mitochondrial dynamics and mitophagy contribute to the development of disease progression in TBI. This pilot project tested the central hypothesis that sex-specific differences in mitochondrial stress response may contribute to sexual dimorphism in TBI outcomes.

The role of estrogens in the cognitive deficits resulting from methamphetamine use, Monserrat Armenta-Resendiz, Ph.D.: Addiction to methamphetamine (METH) is a serious health problem that involves significant impairments in cognitive and executive functions. Females and males differ in their response to METH use. However, there is a gap of knowledge regarding the differences associated with gender in cognitive processes and executive functions following repeated METH administration. Using electrophysiological recordings ex vivo and behavioral tasks in rats, the hypothesis that estrogens decrease dopamine concentration in the PFC, thus having a neuroprotective role ameliorating the cognitive deficits, sensitization and PFC hypoactivity produced by repeated METH administration, was tested.

Sex-specific role of perineuronal nets in chronic METH-induced hypofrontality and cognitive deficits, Ahlem Assali, Ph.D.: Due to the exclusion of females from research and clinical studies in the past, multiple drugs used in females were inefficient or over-dosed, compared to males. This pilot project investigated perineuronal nets(PNNs)-related mechanisms underlying methamphetamine (METH)-induced hypofrontality and cognitive deficits in both males and females. Despite the fact that females may not display an increase in PNNs density in response to chronic METH, and since PNNs formation has been linked to increased PV+FSI activity, the hypothesis that diluted ChABC to slightly digest PNNs in the female PFC could induce a partial rescue of METH-induced cognitive deficits and hypofrontality in female rats was tested.

T-cell regulation of cardiac physiology and cognitive decline in women, Kristine DeLeon-Pennell, Ph.D.: Post-menopausal women have a two-times higher risk of developing cardiovascular disease compared to pre-menopausal women. For women who have a heart attack (myocardial infarction or MI), there is a twofold higher chance of decline in cognitive function. The goal of this SCORE pilot project was to understand how hormonal regulation of CD8 T-cells regulate the wound healing response after MI and can promote impaired cognitive decline. The central hypothesis was that CD8 T-cells are direct and indirect regulators of cognitive decline after MI through hormonal mechanisms. This was the first proposal to integrate multidisciplinary approaches to evaluate hormonal regulation of CD8 T-cells in the MI setting, and added to the understanding of critical mechanisms underlying adverse effects of the adaptive immune response in cognitive function after MI.

Sex, opiates, & prefrontal cortex: Progestin suppression of relapse to opiate seeking in females, Elizabeth Doncheck, Ph.D.: There are currently few effective treatments that can prevent relapse in opioid use disorder (OUD).  This is especially alarming for women as clinical observations imply that females are more vulnerable to relapse than their male counterparts.  However, relapse vulnerability in females co-varies with the ovarian hormone cycle such that peak levels of progesterone and, more specifically, its metabolite allopregnanolone appear to confer protection against relapse.  The goal of this pilot project was to identify treatment targets by determining the underlying mechanisms whereby allopregnanolone provides protection against relapse in women with OUD.  Using state-of-the-art preclinical techniques such as two-photon microscopy, how allopregnanolone regulates the neural circuitry that governs relapse behaviors was investigated.  

Sex differences in stress-induced ethanol self administration in C57/BL6J mice, Anny Gano, Ph.D. & Courtney King, Ph.D.: This project used a novel preclinical model to examine sex differences in stress-induced relapse behavior. This model introduced an alternative to typical reinstatement protocols by assessing both craving-like ("seeking") responses as well as stress-driven alcohol consumption, which may offer excellent face, constructive, and predictive validity to relapse behavior seen in individuals with alcohol use disorder.  Additionally, a growing literature suggests that the ovarian hormone progesterone, which fluctuates naturally during the menstrual cycle in females, may play a key role in sex differences observed in stress reactivity and substance use. These effects can be mediated by the progesterone metabolite allopregnanolone (ALLO). This work also examined potential sex differences in the relationship between levels of neuroactive steroid ALLO and stress-induced relapse behavior. 

Investigating neural and microbiome sex differences in adolescent alcohol use, Anna Kirkland, Ph.D.: This pilot project investigated potential neural and microbiome sex differences within binge drinking adolescents as compared to non-drinking controls. The project built upon baseline data collected from an on-going adolescent alcohol pharmacotherapy trial (K23 AA025399) by adding a control group to analyze the sex-specific effects of heavy alcohol use. This work was significant for the adolescent alcohol use disorder (AUD) field because it will help to 1) understand SABV related neural and microbiome alterations due to heavy alcohol use, and 2) to help identify potential high-yield pharmacological treatment targets for adolescents with AUD.

Endocannabinoid dysregulation in cannabis dependence and acute cannabis withdrawal, Erin Martin, Ph.D.: Endocannabinoids regulate several key homeostatic processes (e.g. eating, sleep, mood) that are negatively impacted in cannabis withdrawal, particularly in women. With this pilot project looked to examine the effects of heavy cannabis use and acute cannabis withdrawal on peripheral endocannabinoid levels in both sexes, and to determine if the degree of change in endocannabinoid levels during withdrawal vs. heavy use is associated with severity of cannabis withdrawal symptom expression. Outcomes from this project could be used to inform sex-specific pharmacotherapeutic strategies for cannabis use disorder.   

Sex specific differences in cross-sensitization between THC and heroin seeking and withdrawal, Daniela Neuhofer, Ph.D.: The current opioid epidemic highlights the need for alternative pain treatment strategies and cannabis is becoming widely legalized for medical use, including pain management. Cannabis could serve as a partial therapeutic alternative to opioids but it is not clear whether a history of chronic THC increases the risk of developing of opioid use disorder (OUD). This pilot project utilized a rodent model to systematically investigate 1) whether a history of THC self-administration modulates different stages of heroin intake, withdrawal and craving, 2) whether these effects of THC pre-exposure are sex-specific and 3) neuroadaptations in brain regions involved in OUD.

Establishing a role for Arc as a molecular mechanism of sex differences in anxiety-like behavior, Rachel Penrod-Martin, Ph.D.: Anxiety disorders are the most common mood disorders, and are experienced by females at higher rates than males.  While there are many pre-clinical studies of anxiety, few of them focus on the underlying neurobiology that may drive sex differences in anxiety. This project used experiments to characterize sex-specific patterns of brain activation produced by anxiety experience, a key step in understanding if there are sex-differences in how the brain processes and responds to anxiety. These findings may help focus attention to the brain regions most likely to be driving anxiety in the two sexes. Another aspect of this project was to understand how sex hormones (estrogen, progesterone) influence anxiety behavior, brain activation, and the expression of proteins in the brain that serve as the connection between brain activity and behavior. These findings might help determine if there are sex-specific mechanisms regulating anxiety and help target those mechanisms to improve anxiety symptoms.

Initial intervention efficacy, cortisol and oxytocin among pregnant women with PTSD, Mary Shapiro, Ph.D.: This project aimed to adapt and test a brief computer-assisted intervention (psychoeducation + skills) for pregnant women with elevated PTSD symptoms. In this open trial pilot study, pregnant women in their first trimester were invited to participate if they endorsed elevated PTSD symptoms. Oxytocin and cortisol were measured at baseline, one month post-intervention, three months post-intervention, and post-delivery to inform the relationship between these hormones, PTSD symptoms, and peripartum/postpartum outcomes. In addition to receiving the psychoeducation and skills intervention during their first trimester, women were offered a “booster session” intervention following delivery to enhance utilization of skills during a critical period for maternal mental and physical health outcomes. 

Applications are not currently being accepted.