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Principal Investigator: Kayla Retallick-Townsley
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $30,103
Funding agency: National Institute of Mental Health
There is an urgent need to decipher the complex polygenic risk architecture of neuropsychiatric and
neurodevelopmental disorders. Most disease-associated common variants are non-coding. Candidate risk loci
in noncoding regions are often regulatory elements, such as enhancers and promoters, that may modulate
transcriptional activity of key genes contributing to one or many endophenotypes. The functional impact of
most disease-associated non-coding variants remains unknown. Enhancers are known to underlie cell-type
specific patterning of gene expression influencing cellular development and responses to environmental
conditions. Candidate regulatory sequences (CRS) associated with genetic risk are likely key drivers of
underlying endophenotypes and represent potential therapeutic targets. Over the past decade, large-scale
identification of regulatory sequences has expanded our awareness and highlighted their importance yet
functional characterization of regulatory elements on a meaningful scale remained inaccessible. Only with
contemporary advances in high-throughput sequencing and large-scale screening techniques, such as the
Massively Parallel Reporter Assay (MPRA), has characterizing the growing list of non-coding risk loci en
masse become feasible. I will apply a MPRA in hiPSC-derived brain cells to identify psychiatric risk variants
within CRS that demonstrate cell-type specific transcriptional activity. Additionally, I wi/1 lool< at the interactions
ol pre-natal stress and inflammation with genetic risl< and consequent susceptibility to negative mental health
later in life. There is sufficient evidence correlating fetal environmental factors with neurodevelopmental
trajectories. Stress or inflammation during pregnancy has been linked to mental health outcomes in the
offspring. The influence of pre-natal environmental factors on brain-related CRSs may explain correlations with
Maternal-Immune Activation (MIA) and increased susceptibility to stress and negative health trajectories of the
offspring. Biological mechanisms underlying MIA may contribute to this increased susceptibility. Using MPRAs,
I will identify risk variants within brain-related CRS that confer greater susceptibility, or resilience, to
environmental stressors. By assessing environmental interactions during development, we will look at
contributions to risk that precede later-life traumatic experiences or symptom presentations. This research will
take place under the Mount Sinai Neuroscience Training Program. Mount Sinai's Department of Neuroscience
currently ranks 2nd nationally in NIH funding. Nearly 5,000 ft2 of space are allocated to the Training Program
within the Neuroscience Department and Friedman Brain Institute. There is, additionally, ~100,000 ft2 that
house the Department's and the lnstitute's research programs and 4,500 ft2 dedicated to Institutional CORE
facilities. This fellowship would support my journey to become a multidisciplinary, translational principal
investigator by providing training in four major areas: Scientific Excellence. Scientific Alliance. Academic
Scholarship. and Scientific Leadership.
Terms: <(TNF)-α><0-11 years old><21+ years old><ASD><Adult><Adult Human><Aeroseb-HC><Affect><Anorexia Nervosa><Anxiety Disorders><Architecture><Area><Assay><Astrocytes><Astrocytus><Astroglia><Atlases><Attention Deficit Disorder><Autism><Autistic Disorder><Awareness><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bioassay><Biological><Biological Assay><Bipolar Affective Psychosis><Bipolar Disorder><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Cachectin><Cetacort><Child><Child Youth><Children (0-21)><Complex><Core Facility><Cort-Dome><Cortef><Cortenema><Cortisol><Cortispray><Cortril><Cues><Data><Data Analyses><Data Analysis><Data Set><Dedications><Dermacort><Developing fetus><Development><Diagnostic><Disease><Disorder><Distal><Dorsal><Dose><Drug usage><Drugs><Early Infantile Autism><Eldecort><Elements><Encephalon><Encephalon Diseases><Engineering / Architecture><Enhancers><Environment><Environmental Factor><Environmental Risk Factor><Expression Signature><Fellowship><Fetal Development><Functional RNA><Funding><Gene Expression><Gene Expression Profile><Gene Transcription><Gene variant><Genes><Genetic><Genetic Risk><Genetic Transcription><Genetics-Mutagenesis><Genomics><Gestation><Glutamates><Goals><HPGF><Health><Hepatocyte-Stimulating Factor><Heritability><High-Throughput Nucleotide Sequencing><High-Throughput Sequencing><Human><Hybridoma Growth Factor><Hydrocortisone><Hydrocortone><Hytone><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune Cell Activation><In Vitro><Infantile Autism><Inflammation><Inflammatory><Institution><Interleukin-6><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Kanner's Syndrome><L-Glutamate><Lateral><Leadership><Libraries><Life><Link><Logic><MGI-2><Macrophage-Derived TNF><Major Depressive Disorder><Manic-Depressive Psychosis><Medical><Medication><Mental Health><Mental Hygiene><Mental disorders><Mental health disorders><Mind><Modeling><Modern Man><Molecular><Monocyte-Derived TNF><Mutagenesis><Mutagenesis Molecular Biology><Myeloid Differentiation-Inducing Protein><NIH><National Institutes of Health><Nerve Cells><Nerve Unit><Neural Cell><Neural Development><Neurocyte><Neurodevelopmental Disorder><Neurological Development Disorder><Neurons><Neurosciences><Neuroses><Neurotic Disorders><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nutracort><Outcome><PTSD><Pathology><Pathway interactions><Pattern><Pharmaceutical Preparations><Physiologic><Physiological><Plasmacytoma Growth Factor><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Predisposition><Prefrontal Cortex><Pregnancy><Principal Investigator><Proctocort><Psychiatric Disease><Psychiatric Disorder><Psychological Health><Psychoneuroses><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Regulatory Element><Reporter><Research><Risk><Risk-associated variant><Schizophrenia><Schizophrenic Disorders><Scholarship><Stress><Susceptibility><Symptoms><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Techniques><Testing><Therapeutic Intervention><Toxic effect><Toxicities><Training><Training Programs><Transcription><Translating><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><United States><United States National Institutes of Health><Untranslated RNA><Variant><Variation><Work><adulthood><adverse childhood events><adverse childhood experiences><allele variant><allelic variant><appropriate dose><astrocytic glia><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><biologic><bipolar affective disorder><bipolar disease><bipolar illness><bipolar mood disorder><brain cell><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cell type><cellular development><clinical depression><clinical predictors><data interpretation><dementia praecox><developmental><disease risk><disorder risk><drug use><drug/agent><early childhood><endophenotype><environmental risk><environmental stresses><environmental stressor><experience><fetal><fetal stress><gene expression pattern><gene expression signature><genetic diagnosis><genetic disorder diagnosis><genetic variant><genomic variant><glutamatergic><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><immune activation><improved><in silico><in vitro activity><induced human pluripotent stem cells><insight><interest><interferon beta 2><intervention therapy><kids><late life><major depression><major depression disorder><manic depressive disorder><manic depressive illness><mental illness><multidisciplinary><neurodevelopment><neurodevelopmental disease><neuronal><neuropsychiatric disease><neuropsychiatric disorder><neurotic><neuroticism><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><noncoding><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><offspring><optimal drug dosage><optimal drug dose><pathway><post-trauma stress disorder><postnatal><posttrauma stress disorder><prenatal><prenatal influence><prenatal stress><progenitor cell model><progenitor model><programs><promoter><promotor><psychiatric illness><psychological disorder><resilience><resilient><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><schizophrenic><screening><screenings><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><therapeutic target><trait><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translational impact><translational opportunities><translational potential><traumatic neurosis><unborn><youngster>