Funding
Cohorts of neurons are organized into anatomically specialized regions that are functionally connected by neural circuits. Allocating distinct types of neurons from uncommitted progenitor cells and the precision of neuronal connectivity requires the coordination of cell fate programming, differentiation, and neural circuit formation. I am interested in how genes and signaling pathways function at specific developmental stages to control these processes. My lab studies these mechanisms in the thalamus, striatum, and dopamine system because these regions regulate perception, sensation, sleep, motivation, and movement and are affected in complex brain disorders including autism, epilepsy, and schizophrenia. Using genetic approaches in mice, we ascertain how neuronal subtypes are established and become functionally connected. We also determine how mutations induced at specific embryonic stages affect brain development and cause complex behavioral phenotypes. Our knowledge of developmental mechanisms is being used to advance stem cell and pharmacological therapies to ameliorate brain disease.
CURRENT FUNDING
NEW FUNDING!
DOD-CDMRP Idea Development Award-Optional Nested Postdoctoral Traineeship
GRANT11448144
Dates: 2014-2017
Timing of Mosaic Gene Deletion in Mouse Blastocysts and Multitissue Disease Development in Tuberous Sclerosis
Role: Principal Investigator; Total Award: $575,000 (direct costs)
The major goals of this project are to mutate Tsc1 in single blastomeres during early embryonic development in mice to induce mosaicism with temporal control. This is advantageous because we will isolate critical time periods in which mosaic Tsc1 inactivation is most pathogenic. By simultaneously marking mutant cells with a conditional reporter, we will conduct detailed cross-tissue clonal analysis in individual mice to identify how the same genetic insult (bi-allelic Tsc1 loss of function) affects different cell types and tissues. Finally, our mosaic deletion strategy allows us to mimic human TS mosaicism and human TS disease phenotypes in a way that has not yet been achieved.
Simons Foundation Autism Research Initiative Annual RFA (2013)
SFARI ID#: 275701
Dates: September 01, 2013-August 31, 2015
Linking genetic mosaicism, neural circuit abnormalities and behavior
Role: Principal Investigator; Total Award: $250,000 (direct costs)
The major goals of this project are to ellucidate how mosaicim dysequilibrium affects brain development and amplifies the phenotype arising from a small number of mutant neurons.
Brown Institute for Brain Science Pilot Grant
4-63662
Date: 2013-2014
A bioengineered model of stem cell manipulation and cell transplantation for neurological disorders
Role: co- Principal Investigator; Total Award: $30,000 (direct costs)
The major goals of this project are to establish a tightly controlled experimental system to test how changing conditions can advance stem cell derived neurons for engraftment and to track cell behaviors after transplantation. This strategy will allow us to optimize experimental design and to test parameters of stem cell manipulation for optimizing transplanting cells in vivo.
DOD-CDMRP Idea Development Award
TS110083
Dates: 2012-2015
Temporal loss of Tsc1: Neural development and brain disease in Tuberous Sclerosis
Role: Principal Investigator; Total Award: $450,000 (direct costs)
The major goals of this project are to identify critical windows of brain development that are affected by the loss of Tsc1 and mTOR dysregulation during embryonic development and to ascertain the impact of mTOR inhibition developing neurons during normal development and in Tuberous Sclerosis.
NIH/NCRR/NIGMS
8P20GM103468-04 (701-1960 sub-award, PI: Zervas, M)
RI Hospital COBRE Center for Stem Cell Biology
Competitive Proposal Submission for Full Project
Dates: 2010-2015 (renewed annually)
Determining the transcriptional regulation and cell signaling events that shape the molecular identity of dopamine neuron progenitors and specify subtypes of midbrain dopamine neurons
Role: Principal Investigator; Total Award: $450,000 (direct costs thus far)
The major goals of this project are to: 1. Elucidate the molecular identity of dopamine neuron progenitors; 2. Determine the genetic basis of dopamine neuron heterogeneity; 3. Investigate the role of WNT, SHH, and FGF8 signaling in establishing the molecular idenity cell and fate specification of dopamine neuron progenitors from embryonic stem cells.
COMPLETED FUNDING (reverse chronological order)
DOD-CDMRP Exploration Hypothesis Development Award
TS100067
Dates: 2011-2013
Determining changes in neural circuits in Tuberous Sclerosis
Role: Principal Investigator; Total Award: $100,000 (direct costs)
The major goals of this project are to ascertain how adult thalamocortical circuits and physiology are altered in the absence of Tsc1 in thalamic neurons.
P30GM103410 (Sub-award PI: Zervas, M)
NIH COBRE award to be used in core facilities to support the work of the Brown Stem Cell Group.
Dates: April 2012-March 2013
Role: Principal Investigator; Total Award: $25,000 (direct costs only)
Determining the dynamic molecular architecture that regulates dopamine neuron diversity
The major goal of this award is to develop novel genetic tools to evaluate how Wnt1 and Lmx1a converge in progenitors to shape midbrain dopamine neuron diversity in vivo.
Richard B. Salomon Faculty Research Award
2-34310
Date: 2010
Genetic dissection of midbrain dopamine neuron diversity
Role: Principal Investigator; Total Award: $15,000 (direct costs only)
The goal of this project is to identify novel transcriptional regulators of dopamine neuron diversity using mouse genetic mutants, fluorescent activated cell sorting and microarray.
NESDB 2011 Meeting Award
No Number
Date: March 25-27, 2011
Northeast Regional Meeting of the Society for Developmental Biology, Marine Biological Laboratory
Role: Meeting Organizer and PI; Total Award: $28,000 (direct costs only)
The award sponsored the 2011 NESDB regional metting, which had the following goals: 1. Promoting a multidisciplinary symposia celebrating novel findings in developmental biology, 2. Expanding graduate student and postdoc interest in developmental biology, 3. Expanding the membership for the Society for Developmental Biology.
Brown University Brain Science Program Pilot Research Grant
No number
Date: 2007
Conditional streptavidin and neuron-specific targeting of biotin conjugates in vivo.
Role: Principal Investigator; Total Award: $15,000 (direct costs only)
The goal of this project was to establish generate a novel transgenic reporter line that expresses both streptavidin and eGFP. The line was established and validated.
The Rhode Island Foundation Medical Research Award
Dates: 2007
Genetic neuroanatomy of substantia nigra dopamine neurons
Role: Principal Investigator; Total Award: $10,000 (direct costs only)
The goal of this project was to establish a high resolution map of midbrain dopamine neuron subtype distribution in the adult mouse brain. The goals of this project were met.
NIH Ruth L. Kirschstein National Research Service Award
F32HD43533
Dates: 2003-2006
Lineage restriction and development of the midbrain and cerebellum
Role: Principal Investigator, Postdoctoral fellow; Total Award: $150,000 (direct costs)
The goal of this project was to develop the genetic inducible fate mapping approach to mark and track genetic lineages in vivo. The goals of this project were met.