2010 — 2012 |
Farrell, Martilias Stephen |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Cell Type Specific Control of Neuronal Signaling @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): Dysfunctional neuronal circuits are thought to be responsible for neuropsychiatric disorders, including obsessive-compulsive disorder, Parkinson's disease and addiction. G protein-coupled receptors (GPCRs) differentially modulate the activity of neuronal circuits by interacting with different G proteins, (e.g. Gs, Gi, and Gq-families), and these receptors are well-established drug targets. Distinct subpopulations of neurons comprising these circuits often express similar receptor subtypes, making it impossible to create drugs that selectively target receptors in specific circuits. In order to determine how receptors might modulate neuronal circuits, it is necessary to selectively activate GPCR signaling in a specific neuronal population in vivo. For the past two decades, efforts have been made to create tools to selectively manipulate GPCR signaling in distinct neuron populations - from small molecule ligands to genetic deletion - but these approaches have off-target effects. These off-target effects effectively eliminate the possibility to determine how GPCR signaling in a specific neuronal population affects circuitry function. A promising advancement to enable this specific manipulation is the development of the Designer Receptors Exclusively Activated by Designer Drug (DREADD) family of receptors. The objective of this proposal is to validate this recently created tool in vivo using a transgenic mouse expressing the Gs DREADD in a specific population of neurons in the striatum. Specific Aim 1 will validate the tool by determining whether the Gs DREADD activates canonical Gs signaling pathways by measuring cAMP accumulation, ERK1/2 phosphorylation, DARPP-32 phosphorylation, and c-Fos expression. Specific Aim 2 will validate the physiological relevance of the Gs DREADD-induced signaling by assessing its effects on animal behavior. The completion of this proposal will provide neuroscientists a powerful new tool to exclusively modulate GPCR signaling in specific neuronal populations. PUBLIC HEALTH RELEVANCE: To understand how drugs work in the brain, scientists need to be able to manipulate certain components of the brain in a very precise manner. This proposal will validate a new tool designed to provide an unprecedented level of specificity to scientists. Information gained using this tool will yield new insight into brain function and may lead to development of new drugs for treating neuropsychiatric diseases.
|
0.946 |
2016 — 2019 |
Farrell, Martilias Stephen |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
The Genomics of Highly Treatment Resistant Schizophrenia @ Univ of North Carolina Chapel Hill
PROJECT SUMMARY / ABSTRACT My long term goal is to lead an independent research laboratory that translates psychiatric genetics findings into the development of novel therapeutics. My previous training in neuropsychopharmacology brought me to the forefront of contemporary psychiatric drug discovery efforts where I realized that novel therapeutic development is needed. Psychiatric genetics has the potential to uncover novel drug targets and treatment strategies. In order to effectively translate genetic findings to therapeutic drug development, I need the ability to analyze and interpret genetic findings in order to prioritize research and development efforts. My immediate career goal is to obtain the skill set necessary to use genomics data to advance psychotherapeutic development. The proposed 4-year career development award will provide an immersive training opportunity in psychiatric genetics that will enable me to design, execute, analyze, and interpret psychiatric genetic research. The proposed research project investigates the genomics of schizophrenia (SCZ) in a sample of highly treatment resistant subjects. These individuals are actively treated, adherent to prescribed medications, reside in a protected environment, do not abuse drugs, and yet many have been severely psychotic for years. The primary goal is to screen a subject?s genome for rare variation that can cause a clinical presentation initially indistinguishable from SCZ. We hypothesize that highly treatment resistant SCZ subjects have rare genetic mutations of strong effect, such as a Mendelian disease. Analysis of a large and notably severe SCZ sample will provide a rigorous test of this hypothesis. Positive findings could dramatically alter the clinical impact of SCZ genomics due to the availability of effective treatments for some disorders. First, we will establish our sample by obtaining consent, then phenotyping and collecting blood samples of patients. Second, we will perform high-throughput genotyping of these samples using whole exome sequencing and DNA microarrays. Third, we will screen these genomic data for rare variants of strong effect relating to their primary diagnosis and their pharmacological treatment. We will also look for and report any secondary findings. Prior to returning our findings to the medical team, the results will be verified by a CLIA-certified laboratory. Finally, we will identify rare variation for future studies (R01) and analyze the data for variation associated with highly treatment-resistant SCZ. In addition to the scientific and therapeutic benefits inherent in this work, this project provides an immersive training program in human genomics studies that aligns with my career goals. In addition to the training provided by the proposed research, I will also undertake an extensive training plan involving mentorship by leaders in the field of statistical genetics, bioinformatics, and the ethical, legal and social implications of medical genetics. Due to my strong background in neuropsychopharmacology, I will be able to use the skills acquired in the proposed project to launch into an independent research career investigating the therapeutic potential of psychiatric genomics findings. Furthermore, this project will provide a wealth of preliminary data for a subsequent R01 which will be prepared and submitted during year 4 of this training plan.
|
0.946 |