Rachel Hill

Dr

Accepting PhD Students

PhD projects

Title: Understanding the role of ARX in psychiatric disorders Supervisors: Rachel Hill and Anna Schroeder This project stems from a recent breakthrough finding in our laboratory whereby we identified a new mutation in a gene called ARX in a patient with schizophrenia. We now wish to understand the functional consequence of this mutation. We are generating, using CRIPR-CAS9 technology a mutant mouse with our identified mutation inserted into its genome. This project will involve behavioural and cellular experiments to characterise the effects of this new mutation on CNS function in mice. This exciting new project is the first in the world to characterise variants in the ARX gene with relevance to schizophrenia. Title: Using single-nuclei RNA-Sequencing to uncover novel candidate genes and/or signalling pathways that are altered in people with schizophrenia. Supervisors: Prof. Suresh Sundram and Dr Rachel Hill The cause of schizophrenia is not yet known but there is undoubtedly a strong genetic component. However, there remains a frequent lack of reproducibility, across different research groups and patient cohorts, of significant associations between specific genes and schizophrenia risk. This is particularly true in studies assessing mRNA expression in post-mortem human brain tissue. This variability may be due to a number of factors associated with post-mortem tissue, e.g. cause of death, agonal state, age, gender, etc. Another major contributing factor to this variability is that studies tend to use extracts of whole tissue, including a mixture of different populations of cells. How each individual cell functions is dependent upon its transcriptional program. Therefore, to analyse homogenates of multiple cell types, with different functions and thus different transcriptional programming is non-specific – and thus individual cell specific signals are lost. Here, very recent advances in single-nucleus RNA sequencing [1] will allow us to probe the cell specific transcriptome of patients with schizophrenia, adding an exceptional layer of specificity to the understanding of schizophrenia pathology. Single Nucleus RNA-Sequencing (DroNc-Seq): In conjunction with Monash Genomics core facility, this project will test the above mentioned novel methodology recently published in Nature Methods [1]; Massively parallel single-nucleus RNA-seq with DroNc-seq (droplet nuclei sequencing) in human postmortem tissue from schizophrenia patients. This technique isolates nuclei from human post-mortem tissue then co-encapsulates individual nuclei with a barcoded bead within a nanolitre-scale oil droplet. This bar-coded bead retains a molecular memory of the identity of the cell from which the mRNA transcript was isolated. This is referred to as a STAMP (Single-cell Transcriptomics Attached to Microparticles). Thousands of STAMPs are collected for reverse transcription, amplification and sequencing with the individual barcodes within each STAMP allowing identification of each transcript’s cellular origin. In preliminary studies we have shown successful co-encapsulation of nuclei isolated from frozen human brain (prefrontal cortex) with the barcoded beads. This project will expand this in a large cohort of tissue samples, then process RNA for RNA-Seq analysis using the Illumina HiSeq3000 instrument at the Monash Health Translation Precinct genomics facility. This study using highly innovative techniques at the forefront of cellular genetics will uncover cell-type specific detail on the genetic pathology of schizophrenia with great potential for novel targets to be identified and assessed in preclinical animal model testing. Title: Using advanced genetic tools to guide the future of precision medicine in psychiatry Supervisors: Prof. Suresh Sundram and Dr Rachel Hill Schizophrenia is a psychiatric disorder that is characterized by frightening hallucination, and delusions as well as severe cognitive and mood disturbances. It is a developmental disorder that emerges during late adolescence / early adulthood and there is currently no cure. There is strong support for a genetic component to schizophrenia, and current findings from genome-wide association studies (GWAS) have unearthed many low-penetrance mutations that marginally increase risk as well as a very small number of high-penetrance mutations that are incredibly rare. Importantly, more recently it has been shown that genetic mutations associated with schizophrenia are shared across other major psychiatric disorders, such as bipolar disorder, suggesting that perhaps psychiatry needs to move away from traditional diagnosis and look toward a biological diagnostic tool which may then aid in targeted biological treatments. Before such a tool can be created we need to better understand the familial patterns of specific genetic anomalies and determine how they are expressed across multiple family members, and what their biological function is. This project will be part of a large scale human clinical genomics study to identify families with multiple members affected by a psychiatric disorder. Biological samples from affected and non-affected family members will be collected for whole exome genetic sequencing to identify genetic mutations that increase risk for psychiatric disorders. By analysing multiple family members we may then ascertain which genetic anomalies are associated with psychiatric disorders and which are associated with specific disorders. The project will involve recruitment of participants and biological sample prep and analysis. The biological relevance of identified genetic mutations will then be studied in our neuroscience laboratories using preclinical cellular and animal models.

20032020

Research output per year

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Research Output

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Review Article
2019

Hypothalamic-pituitary-gonadal axis dysfunction: An innate pathophysiology of schizophrenia?

Du, X. & Hill, R. A., 1 May 2019, In : General and Comparative Endocrinology. 275, p. 38-43 6 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

2 Citations (Scopus)
2018

On the developmental timing of stress: Delineating sex-specific effects of stress across development on adult behavior

Schroeder, A., Notaras, M., Du, X. & Hill, R. A., 1 Jul 2018, In : Brain Sciences. 8, 7, 29 p., 121.

Research output: Contribution to journalReview ArticleResearchpeer-review

Open Access
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9 Citations (Scopus)
2016

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

Hill, R. A., Aug 2016, In : Neuroscience and Biobehavioral Reviews. 67, p. 41-56 16 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

25 Citations (Scopus)
2015

7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders

Du, X. & Hill, R. A., 25 Apr 2015, In : Neurochemistry International. 89, p. 170-180 11 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

16 Citations (Scopus)

A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review.

Notaras, M., Hill, R. A. & van den Buuse, M., Apr 2015, In : Neuroscience and Biobehavioral Reviews. 51, p. 15-30 16 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

80 Citations (Scopus)

The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy.

Notaras, M., Hill, R. A. & van den Buuse, M., Aug 2015, In : Molecular Psychiatry. 20, 8, p. 916-930 14 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

116 Citations (Scopus)
2014

BDNF–TrkB signaling as a therapeutic target in neuropsychiatric disorders

Du, X., Wu, Y. C. & Hill, R. A., 6 Oct 2014, In : Journal of Receptor, Ligand and Channel Research. 7, p. 61-79 19 p.

Research output: Contribution to journalReview ArticleOtherpeer-review

Open Access
2 Citations (Scopus)
2013

Sex differences and the role of estrogen in animal models of schizophrenia: interaction with BDNF

Wu, Y. C., Hill, R. A., Gogos, A. & van den Buuse, M., 22 Oct 2013, In : Neuroscience. 239, p. 67-83 6 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

53 Citations (Scopus)
2012

Interaction of sex steroid hormones and brain-derived neurotrophic factor-tyrosine kinase B signalling: relevance to schizophrenia and depression.

Hill, R. A., Dec 2012, In : Journal of Neuroendocrinology. 24, 12, p. 1553-61 8 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

22 Citations (Scopus)
2009

Estrogens, brain, and behavior: Lessons from knockout mouse models

Hill, R. A. & Wah, C. B., 1 May 2009, In : Seminars in Reproductive Medicine. 27, 3, p. 218-228 11 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

28 Citations (Scopus)

Estrogens, Brain and Behavior:Lessons from mouse models

Hill, R. A. & Boon, W. C., 2009, In : Seminars in Reproductive Medicine. 27, 3, p. 218-228

Research output: Contribution to journalReview ArticleResearchpeer-review

2005

Estrogen - The good, the bad, and the unexpected

Simpson, E. R., Misso, M. L., Hewitt, K. N., Hill, R. A., Boon, W. C., Jones, M. E., Kovacic, A., Zhou, J. & Clyne, C., 2005, In : Endocrine Reviews. 26, 3, p. 322-330 9 p.

Research output: Contribution to journalReview ArticleResearchpeer-review

202 Citations (Scopus)