Document text
Principal Investigator: Martin Tran
Organization: CALIFORNIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $48,974
Funding agency: National Eye Institute
Project Summary/Abstract
The overarching goal of this proposal is to understand how the stereotypical structure of retina forms
during embryonic development. Towards this goal, this proposal seeks to develop novel molecular recording
technologies that allow the reconstruction of lineage history based on endpoint measurements. This method
leverages genome editing techniques to stochastically create heritable mutations within synthetic barcode
arrays that accumulate edits over time. Because readout of these arrays is compatible with spatial
transcriptomics technologies, these methods when combined will allow the simultaneous capturing of
transcriptional cell state, lineage relationships, and spatial position of single cells within retina tissue. The
resulting lineage tree datasets will then be analyzed using a novel statistical tool termed Lineage Motif
Analysis, a computational approach to identify all significantly over- or under-represented cellular patterns. This
approach systematically enumerates all possible arrangements of observed fates on progressively larger
subtrees and then compares their frequencies to those expected in a null model based on uncorrelated cell
fate between cell divisions. Lineage trees will reveal how birth-order of cell types is regulated on the clonal
level and lineage motifs will reveal the extent to which lineage in the retina is stochastic or preprogrammed.
Furthermore, lineage motifs represent direct insight into the “rules” that govern how the retina forms during
development, and provide a way to describe how such “rules” change in different contexts like disease or
pharmacological perturbation. The datasets and analysis proposed here will inform the development of new
therapeutic strategies for regenerative medicine to treat retinal diseases that lead to blindness.
My training program outlined here will equip me with the necessary tools and knowledge to (1) carry out
the aims of this proposal and gain novel biological understanding, and (2) advance me towards my career goal
of leading a research team focused on studying the fundamental principles that underlie embryonic
development and disease progression. I will work with Dr. Long Cai, a pioneer in spatial transcriptomics, to
learn imaging and image processing techniques, as well as Dr. Carlos Lois, an expert in neurobiology, to learn
mouse manipulation and surgical procedures. Dr. Elowitz and I will meet regularly to discuss my research
progress, writing plans for paper publications and grants, teaching/mentoring students, and opportunities to
present my research at Caltech and national conferences. As a PhD student at Caltech, I will have access to
leaders well-versed in applying quantitative approaches to study developmental biology, state-of-the-art core
facilities, and cutting-edge coursework in both biology and statistics. By funding the rest of my PhD research,
this fellowship will enable me to uncover the fundamental principles that underlie retina development and set
me up for independence as I transition towards becoming an independent investigator in my later career.
Terms: <21+ years old><Address><Adult><Adult Human><Bar Codes><Biological><Biology><Birth Order><Blindness><Body Tissues><Brain><Brain Nervous System><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Lineage><Cell Signaling><Cell division><Cell-to-Cell Interaction><Cells><Collaborations><Core Facility><Data Analyses><Data Analysis><Data Set><Development><Developmental Biology><Developmental Process><Disease><Disease Progression><Disorder><Doctor of Philosophy><Educational process of instructing><Embryo Development><Embryogenesis><Embryonic Development><Encephalon><Engineering><Expression Signature><Family><Fellowship><Frequencies><Funding><Gene Expression><Gene Expression Profile><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genome><Goals><Grant><Heritability><Heterogeneity><History><Image><In Situ><Individual><Intracellular Communication and Signaling><Investigation><Investigators><Knowledge><Learning><Maps><Measurement><Methods><Mice><Mice Mammals><Modeling><Molecular><Murine><Mus><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Operative Procedures><Operative Surgical Procedures><Paper><Pattern><Ph D student><Ph D. student><Ph. D. student><Ph.D student><Ph.D.><Ph.D. student><PhD><PhD student><PhD. student><Position><Positioning Attribute><Probabilistic Models><Probability Models><Procedures><Process><Publications><RNA Expression><Recording of previous events><Regenerative Medicine><Research><Research Personnel><Researchers><Resolution><Rest><Retina><Retinal Diseases><Retinal Disorder><Role><Sampling><Scientific Publication><Seminal><Series><Signal Transduction><Signal Transduction Systems><Signaling><Spatial Distribution><Statistical Models><Stochastic Processes><Structure><Surgical><Surgical Interventions><Surgical Procedure><System><Teaching><Techniques><Technology><Time><Tissues><Training Programs><Transcription><Trees><Visualization><Work><Writing><adulthood><barcode><biologic><biological signal transduction><career><cell type><conference><convention><data interpretation><developmental><doctoral student><experiment><experimental research><experimental study><experiments><gene expression pattern><gene expression signature><genome editing><genome mutation><genomic editing><histories><image processing><imaging><insight><large scale data><large scale data sets><large scale datasets><model organism><neurobiological><neuronal><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pharmacologic><progenitor><programs><reconstruction><regenerative><resolutions><retina disease><retina disorder><retinal progenitor><retinal progenitor cell><retinal stem cell><retinopathy><scRNA-seq><sibling order><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single molecule><single-cell RNA sequencing><social role><statistical linear mixed models><statistical linear models><statistics><stochastic method><student mentoring><student-led learning><summit><surgery><symposia><symposium><tool><transcriptional profile><transcriptional signature><transcriptomics><vision loss><visual loss><visual stimulus>