The New Jersey Governor's Council for Medical Research and Treatment of Autsim is happy to introduce the gratees for our Concept Project and Felloswship Porgram awards. For more information on the Council's programs and current opportunities, please see our Current Grant Initiatives.
| Name | Institution | Project Title |
| Anat Kreimer, Ph.D. | Rutgers University | Decoding Autism Regulatory Variants Using Computational Genomics in Human iPSC-Derived Neurons. |
| Description: Researchers can read protein coding DNA sequence and predict the amino acid sequence of proteins. However only about 2% of the human genome encodes protein, with most of the genome being non-coding. Noncoding DNA regulates gene expression but until recently it was impossible to “gaze” at non-coding DNA and identify functional sequences. Importantly, thousands of autism mutations map to non-coding sequence, but it remains unknown which of these non-coding variants are functional. This is a very significant gap in our understanding of autism etiology. The goal of this proposal is to identify functional non-coding ASD mutations by leveraging stem cell derived human neurons in combination with new multi-omic and computational approaches. | ||
| James Millonig, Ph.D. | Rutgers University | A p53 Mediated Mechanism for 16p11.2 ASD Hyperproliferation Phenotype. |
| Description: Altered proliferation is an important convergence point for autism risk (5,16,17), but the contributing signaling pathways have yet to be identified. This information is needed to develop new ASD treatments. To define these pathways, the Millonig lab has been studying a small deletion on human chromosome 16 called 16p11.2 (16pDel). The mutation deletes only 28 genes and is one the largest contributors to autism risk (8). 16pDel individuals often have diagnoses suggestive of proliferation defects, including neuroblastoma, a neuronal cancer, and macrocephaly, enlarged head (8,9). We have utilized human stem cells to derive neural progenitor cells (NPCs) and have discovered a reproducible and robust hyperproliferation phenotype in 16pDel individuals with autism. | ||
| Name | Institution | Project Title |
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Peng Jiang, Ph.D. |
Rutgers University | Regulation of Human Forebrain Development by ASD-Associated Cytokines in Human iPSC-derived Cerebral Organoids. |
| Description: Extensive clinical studies have demonstrated that maternal infections, allergies, autoimmune diseases, obesity or pollution during pregnancy increase offspring risk for developing ASD by 2-4 fold. How these conditions enhance the frequency of ASD remains largely unknown. But, one signal that is produced by the maternal immune system that is consistently increased and that can cross the placenta and then cross into the fetal brain is the cytokine interleukin-6 (IL-6). Importantly, published studies using animal models have shown that IL-6 is both necessary and sufficient to cause several behavioral phenotypes associated with ASD. However, prior studies have almost exclusively used murine models, which present challenges to translate those results to human biology considering that human neural progenitors are more complex than those in mice. Therefore, we propose to establish mini-brain cultures comprised of human neural progenitors (from human induced pluripotential stem cells) and then determine how IL-6 exposure alters their production of excitatory vs. inhibitory neurons as well as their capacity to produce non-neuronal cells. These human mini-brains will contain those human NPCs that are present during the end of the 2nd trimester of development, which is when exposure to stimuli that cause maternal inflammation are most likely to increase the probability of a child developing autism. The central premise of this application is that IL-6 alters human NPC gene expression, which skews their specification to glutamatergic excitatory neurons, from inhibitory neurons, and compromises macroglial cell differentiation (i.e. astrocytes and oligodendrocytes). Presently no treatments are available to prevent or to reduce the incidence or severity of ASD; however, drugs targeting the IL-6 pathway are used to treat rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Castleman disease, SARS-Cov2 and others. Clinical and preclinical studies continue to implicate prenatal IL-6 exposure in the etiology of ASD, providing rationale for re-purposing these IL-6 pathway inhibitors for their therapeutic potential. Such treatments could save billions of dollars annually and relieve the suffering of millions of individuals worldwide. | ||
| Chiara Manzini, Ph.D. |
Rutgers University |
Unraveling the diversity of PDE4D signaling to understand the mechanisms of action of PDE4D inhibitors. |
| Description: To date, the treatment options for the main symptoms of autism affecting social interactions and leading to repetitive behaviors mostly rely on behavioral therapy with a psychologist. No drugs can be prescribed to improve social function or learning deficits. Only recently, a clinical trial in individuals with Fragile X Syndrome, the most common genetic cause of autism, has pointed to drugs that block the enzyme phosphodiesterase 4D (PDE4D) as a possible treatment. PDE4D controls how brain cells (neurons) respond to outside signals from other neurons, hormones, and growth factors. However, PDE4D also functions in other cells throughout the body and its specific site of action in neurons is poorly understood. The first goal of our proposal is to define how PDE4D functions at the sites that control communication among neurons, the synapses. Then we will explore its role in the brain region that controls memory, the hippocampus, also studying mice where the Fragile X Syndrome gene has been removed to understand where PDE4D inhibitors are acting. Overall, the proposed research will not only better explain how PDE4D inhibitors function, but also possibly lead to the development of more specific drugs. | ||
| Name | Institution | Project Title |
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Vanessa Bal, Ph.D. |
Rutgers University |
Boosting Engagement and Skill Acquisition through Technology and Personalization: A Pilot Trial of Enhanced Transdiagnostic Behavioral Therapy. |
| Description: Autistic individuals are at high risk for co-occurring conditions, such as depression and anxiety. Yet, there is very little research on treatments to address these difficulties autistic adults. The long-term goal of this project is to expand the availability of programs to promote the mental health and quality of life for autistic adults. To do this, this project focuses on developing ways to improve Group Behavioral Activation Treatment (GBAT) for use with autistic adults. This study will be used to inform final changes to GBAT+ and be used to make decisions regarding the design of future GBAT+ studies to establish if GBAT+ is an effective way to support autistic adults. This project has both immediate and long-term public health impact by providing direct support of autistic adults and contributing to training of psychologists at Rutgers who will go on to support the mental health needs of autistic adults in the community. | ||
| Yu-Lun Chen, Ph.D. |
Kessler Foundation |
Racial, Ethnic, and Language Disparities in Autism Health Service Use among Children in NJ: Assessing Longitudinal Trends of Service Gaps and the Role of Social Determinants. |
| Description: Children with autism require early and ongoing access to multiple medical and therapy services for healthy development and socialization. These health services include primary and specialized medical services (e.g., developmental-behavioral pediatrics and psychiatry) as well as specialized therapy services (e.g., occupational therapy, physical therapy, psychology, and speech therapy). However, research shows that Black and Hispanic/Latino children, as well as children from families with limited English proficiency, have less access to these health services and report more unmet service needs. Given that 45% of New Jersey residents are racial or ethnic minorities and 31% speak a primary language other than English, there may be a large proportion of children with autism in New Jersey who are not receiving the care they need. To understand this critical issue, this study proposes to investigate trends in the use of health services over time among children with autism living in New Jersey. And, it will investigate whether service gaps by race/ethnicity, language preference persist over time and differ by the characteristics of the places where people live. | ||
| Name | Institution | Project Title |
| Christina Simmons, Ph.D. |
Rowan University |
Randomized Pilot Evaluation of Healthcare Professional Training Using a Virtual Reality Training Program for Severe Behavior in Children with Autism. |
| Description: In this project, we will develop and evaluate a virtual reality (VR) healthcare professional training tool that maximizes the effect of critically needed behavioral training for clinicians working with children with autism spectrum disorder who engage in severe unsafe and interfering behavior. The VR training tool addresses access barriers to training by allowing clinicians to practice intervention implementation with individualized feedback in the comfort of their own home at times convenient for their schedule and quality barriers by more closely resembling scenarios clinicians will encounter with their clients than contrived practice opportunities. The proposed customizable VR technology has the potential to (a) be highly impactful for healthcare professionals by teaching sustainable behavioral strategies for addressing severe behavior in the home and community, (b) be efficient and informative for trainers to collect data to support their trainees, (c) contribute to improved child treatment outcomes by preparing clinicians to implement intervention during treatment challenges, and (d) promote greater job satisfaction and long-term retention of healthcare professionals serving children with autism. | ||
| Walter Zahorodny, Ph.D. | Rutgers University |
Detection & Connection – ASD Screening Project. |
| Description:
Every year, more children are identified with Autism Spectrum Disorder (ASD). Most ASD children are diagnosed after 36-months. Children from low income and minority communities are less likely to be evaluated for ASD and less likely to get early intervention program services than affluent and white children. To improve the early identification of young children with ASD and their linkage to services, we propose to implement a new service delivery program, Pediatric Detection + Connection (Ped-D+C) at multiple pediatric programs including primary care clinics, early intervention programs and Women, Infants and Children (WIC). We initiated the Ped-D+C program at a large pediatric primary care practice in Newark. The program was effective in increasing ASD screening and referral to EIP and development specialists. The program used a brief autism screener, the Psychological Development Questionnaire (PDQ-1) as part of the intake and continuity care process and engaged Mom2Mom – a peer support organization to facilitate linkage to early intervention services and comprehensive developmental evaluation. Mom2Mom is a peer-to-peer counseling system staffed by mothers of children with special needs who use their experience on behalf of parents of children who are screen positive. This project will address primary weakness in the process of early ASD identification including detection of ASD using a valid effective screener (PDQ-1) and connection by linking families of at-risk children to services through peer-to-peer support (Mom2Mom). The goals of the study are 1) to increase ASD screening in underserved populations, 2) facilitate linking of at-risk children to EIP services and comprehensive developmental evaluation, 3) reduction of wealth and race-based disparities in ASD identification and 4) provision of evidence regarding the effectiveness of the (Ped-D+C) model. |
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| Name | Institution | Project Title |
| Alessandro Bortolami | Rutgers University | A Novel Murine Model to Study Potassium Channel-Related Autism Spectrum Disorder. |
| Description: Autism spectrum disorder (ASD) is a neurological condition characterized by learning impairment, motor deficits, and restricted repetitive behaviors. ASD can be caused by defects in the brain probably arising as early as gestation. We have found that a protein named KCNB1 causes malformations in the cortex and behavioral defects in mice that resemble typical behaviors of ASD children. Our project aims at studying how KCNB1 protein causes brain malformations and corresponding behavioral deficits. We hypothesize that by studying these mice we can better understand what causes ASD in humans. | ||
| Erin McKenney | Rowan University | Examining Depression, Anxiety, and Trauma in First-Semester Autistic College Students. |
| Description: Depression and anxiety are more common in autistic adults than in the general population, and these mental health concerns have been named by autistic adults as a high priority for future research. Many individuals have identified the transition to college as an especially difficult time point due to changes in routine, social support, and demands. Despite these concerns, there has been very little research exploring what predicts greater mental health problems over time in this population. The current study explores how negative repetitive thinking, social satisfaction, and traumatic sexual experiences predict and maintain depression and anxiety symptoms during the college transition. Additionally, this study explores how common these potential predictors of depression and anxiety are in autistic college students compared to non-autistic peers. It is expected that higher negative repetitive thinking, lower social satisfaction, and experiencing sexual trauma will be related to increased depression and anxiety symptoms, and that both these predictors and the depression and anxiety symptoms will be more common in autistic participants than in non-autistic participants. This work will help to build better prevention and intervention strategies for depression and anxiety in the underserved population of autistic adults, particularly in the college setting. | ||
| Denise Robles | Rutgers University | Modeling Long-Range Connectivity Deficits in ASD using Cerebral Organoids. |
| Description: Autism spectrum disorders (ASD) are highly prevalent, particularly in New Jersey where an estimated one in 35 children are affected. As a spectrum disorder, ASD may severely impact patients’ quality of life and pose a significant socioeconomic burden. Both genetic and environmental factors have been tied to causing ASD. While recent years of research have seen great strides in uncovering specific genetic and behavioral phenotypes at the cellular, molecular, and network circuitry levels, there remains a lack of understanding regarding human- specific pathophysiology. This work focuses on developing a system to recapitulate ASD-relevant pathophysiology using three-dimensional (3D) cerebral organoids (COs) derived from patient-specific human induced pluripotent stem cells (hiPSCs) carrying a genetic mutation in the SETD1A gene known to cause syndromic autism. This novel experimental paradigm combines human stem cell technology and microfabrication bioengineering to recapitulate the long-range projections formed between brain regions during human neurodevelopment. The central hypothesis is that this platform will promote the formation of long-range connections between CO cultures and demonstrate impaired maturation and functional activity in ASD COs. Successful implementation of this proposed work will: 1) allow the elucidation of molecular and cellular mechanisms underlying the long-range connectivity deficits in ASD and the contribution of genetic risk factors; and 2) provide an innovative platform that can be used for drug screening for devising novel therapeutics and treatment regimens through selection of pharmacological interventions, dosing, and frequency of administration. | ||
| Sofia Gonzalez Salinas, Ph.D. | Rutgers University | Cortical Circuits Regulating Social Behaviors. |
| Description: Impaired social interactions are a core symptom in patients with Autism Spectrum Disorders (ASD). Deficient social skills can deeply impact ASD patient’s daily activities including employment, forming affective bonds and could be linked to anxiety and depressive symptoms. While several regions of the brain may be involved in social deficits in ASD patients, the activity of cells in the medial prefrontal cortex (mPFC) may be a critical mechanism to promote healthy interactions. Work in animal models of ASD suggests that social deficits may be caused by altered activity of cells located in the mPFC that are connected with other brain areas. However, the neuronal circuits of the mPFC controlling social behaviors are not well understood. We will study in mice a subpopulation of cells of the mPFC that by projecting to the hypothalamus or amygdala may modulate social interactions. Using state-of-the-art techniques that provide high cellular resolution and time regulation of neuronal activity we will control and record the activity of these two mPFC circuits during social interactions. We hypothesize that increased activity in one circuit and the repression of the other will promote social interactions. Our proposal will provide critical knowledge to understanding the functional basis of social behaviors that might be applied to develop non-invasive strategies that improve social skills in ASD patients. | ||
| Name | Institution | Project Title |
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Mengmeng Jin |
Rutgers University |
Modeling Microglial Dysfunction with Human iPSC Models of Down Syndrome and Autism Spectrum Disorder. |
| Description: Up to 39% of Down syndrome (DS) individuals have autism, or autism spectrum disorder (ASD) (hereafter referred to as DS-ASD), compared to 1% in the typical population. As the brain's resident immune cells, microglia play vital roles in regulating inflammation in the brain and shaping brain development, thereby impacting cognitive functions. Notably, dysregulation of microglial functions is highly associated with the development of ASD. This fact has driven researchers to investigate causal links between microglial dysfunction and ASD. However, very limited information is available on the precise contributions of microglia during brain development in ASD and DS-ASD, as well as the underlying molecular mechanisms. Recent advance in stem cell technology allows researchers to differentiate human induced pluripotent stem cells (hiPSCs) into microglia, which provides unlimited human microglial cells to study their pathophysiology. In this study, we will generate microglia from hiPSCs derived from DS individuals. We propose transplanting the DS human microglia into the mouse brain to further develop a human-mouse chimeric brain model. This new model will allow us to interrogate the pathogenic role of microglia in DS-ASD, by studying the DS human microglia developed in an intact brain environment. Findings from this study may lead to the development of new therapeutic treatments for not only ASD in the DS population but also ASD in the general population. | ||
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Luka Turkalj |
Rutgers University |
Perturbation of Neuronal Proteostasis and Integrated Stress Response in Cc2d1a and Cc2d1a/Cc2d1b Loss of Function. |
| Description: This study aims to investigate how problems with the way brain cells traffic and degrade proteins and respond to protein accumulation can cause neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). It focuses on an important protective pathway called integrated stress response (ISR), which is getting recognized as a common deficit in different disorders associated with ASD and ID. The re-searchers will be studying a gene called CC2D1A, which can cause these disorders when it is not working cor-rectly. They will use brain cells called neurons, which have been modified to not have this gene to study how it affects them. The researchers have three goals for this study: 1) to see how CC2D1A and another gene called CC2D1B help traffic proteins through neurons for degradation, 2) to see how the ISR responds when these genes are not working properly, and 3) to see if there is a connection between protein accumulation and ISR activation in these neurons. The integrated stress response is a promising therapeutic target that could be used in the treatment of different disorders associated with ASD and ID. Therefore, this research could help us to better understand how these disorders develop and aid in developing novel treatment strategies. | ||
|
Le Wang |
Rutgers University | Dissecting the circuits mechanism of ASD-associated NLGN3 and NRXN1 loss-of-function human neurons engrafted in a chimeric mouse model. |
| Description: Autism spectrum disorder (ASD) is a complex neurological condition that affects millions of individuals worldwide. According to the CDC, in New Jersey, the rate of ASD is 1 in every 35 children. The underlying causes of ASD are not well understood, but recent research has suggested that certain genetic mutations increase the risk of ASD in the population. According to Simon Foundation Autism Research Initiative (SFARI), mutations of both NLGN3 and NRXN1 have been linked to ASD. These genes are involved in the formation and function of synapses, the connections between neurons in the brain. In my recent publication, I found that a mutation in NLGN3 that linked to ASD caused aberrant functional changes in a human neuronal model. In this application, the overarching goal of this project is to unravel the mechanisms underlying ASD-associated mutations in NLGN3 and NRXN1 in human neuronal models. I hypothesize that loss-of-function mutations in NLGN3 and NRXN1 lead to a functional deficit in synapse formation and/or function. To test this hypothesis, I will generate functional human excitatory neurons with mutations in both NLGN3 and NRXN1. These neurons will then be engrafted into the prefrontal cortex of chimeric mice, allowing us to study their integration into the mouse brain circuitry. We will use advanced techniques to investigate the synaptic connectivity, activity, and plasticity of the NLGN3 and NRXN1 loss-of-function human neurons compared to control neurons. Utilizing this unique human neuron-mouse chimeric model, we will be able to address the long-term impact of human neurons carrying NLGN3 or NRXN1 mutations in an in vivo environment of neurocircuits. This study has the potential to provide significant implications for the development of effective treatments for ASD, as it will provide critical insights into the cellular and circuit-level mechanisms underlying the condition. Moreover, the use of a chimeric mouse model provides a valuable tool for further investigating the underlying causes of ASD and testing potential therapeutic interventions. | ||
|
Ellen Wilkinson |
Rutgers University | Adapting an evidence-based behavioral activation treatment for depression in minimally verbal autistic adults |
| Description: There is increasing attention to the mental health of autistic people, including research on treatments for disorders like depression. In fact, depression is thought to be even more common in autistic individuals, with prevalence estimates of 23-37% (Hollocks et al., 2019) and at least as common in individuals with intellectual disability (Buckles et al., 2013). Therefore, it is concerning that even though 20-30% of autistic people remain minimally verbal (MV) into adulthood (Howlin et al., 2014; Pickles et al., 2014), there has been very little attention given to the treatment of depression in these people and there are no treatments supported by research. There is one form of depression treatment that has shown promise in being a good fit for people with autism and/or intellectual disabilities: behavioral activation. This treatment does not heavily rely on cognitive and verbal communication abilities, like traditional mental health treatment does. BeatIt is a treatment that uses behavioral activation to treat depression in adults with intellectual disability (Jahoda et al., 2015). It has a focus on identification of pleasurable and meaningful activities, as well as increasing those activities. It includes a support person, who comes to all sessions and when appropriate assists with the activities. Because of these core features, with some adaptation it may be a good depression treatment option for MV autistic adults. The goal of this study is to adapt the BeatIt treatment manual to for use with MV autistic adults and then examine the feasibility of the treatment through a trial. Through collaboration with an interventional development group (3 MV autistic adults and their supporters) and the study team, an adapted manual will be developed (BeatIt-MV). Next, a feasibility trial including 12 MV autistic adults and their supporters will be conducted. To assess any changes, they will complete measures on their mental health and quality of life before, halfway through, and after the treatment. Participants will also provide feedback on the study procedures and treatment. Information collected during both parts of the study will be used to guide future studies to determine whether Beat-MV can be used to treat depression in MV autistic adults. This study is an important step toward addressing the mental health needs of MV autistic adults and supporting their quality of life. | ||
| Name | Institution | Project Title |
|
Wayne Fisher, Ph.D. |
Children’s Specialized Hospital |
New Jersey Autism Center of Excellence. |
| Description: Given the complex presentations and causes of ASD, the variability in response to treatment, and the disparities in clinical services, there has been increased emphasis on the importance of interdisciplinary, translational research informed by the needs and input of individuals with ASD and their families. In this application, we propose to address these complex and unique features of ASD by promoting increased communication and collaboration amongst autism researchers, educators, practitioners, and autistic individuals and their families to (a) improve our understanding of and ability to diagnose and treat ASD, (b) decrease service disparities, and (c) improve health outcomes for all New Jersey individuals and families affected by ASD. The proposed NJACE will facilitate the development of enduring training programs on biomedical treatments and diagnosis of autism for physicians and other healthcare professionals by awarding seed grants (n = 2) to New Jersey investigators to support the development of competitive federal training grants (e.g., T32 applications to NIH). We will facilitate specialized, science-to-practice training in autism diagnosis and management by offering practica and workshops in critical areas of need and by awarding competitive training stipends so that current and future healthcare professionals serving community-based organizations can receive the specialized training, with priority given to healthcare workers serving marginalized groups. We will disseminate critical information and provide continuing education on the latest advances in biomedical research on autism for physicians and other healthcare professionals through an annual conference and bimonthly symposia that will include leading local and national experts in the field. The proposed NJACE, in cooperation with CSH and the Rutgers Clinical Trials Office, will develop a statewide ASD research online database that will facilitate communication between New Jersey researchers and individuals with ASD and their families so that (a) the ASD community receives up-to-date information on the latest scientific advances related to ASD, (b) those affected by ASD can provide direct input and collaboration with researchers to increase the impact and relevance of future research, (c) individuals with ASD and their caregivers will have the opportunity to participate in research, and (d) New Jersey researchers will have increased access to potential research participants. The proposed NJACE will prioritize applications for its research and training grants and presentations for its informational and continuing-education activities that focus on the following: (a) transition to adulthood, including health care, educational pursuits, and employment; (b) developmental support services (e.g., early identification, co-occurring ID); (c) use of data to drive measurable health improvements; (d) identifying and targeting vulnerable populations for interventions to address health disparities; and (e) promotion of collaboration across sectors to develop health policies and achieve health equity. | ||
