2004 — 2005 |
Bhalla, Needhi |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Meiotic Pairing Center Function in C. Elegans @ University of Calif-Lawrenc Berkeley Lab
DESCRIPTION (provided by applicant): The pairing and synapsis of homologous chromosomes during meiosis is an early requirement for proper meiotic chromosome segregation. Defects in meiotic chromosome segregation generally cause the death of resulting progeny, but can also lead to serious developmental disorders, such as Down syndrome. How chromosomes identify, pair and ultimately synapse with their unique homolog is poorly understood. Genetic studies in C. elegans have implicated specific chromosomal regions at one end of each chromosome as potential pairing centers (PCs). I propose to investigate PC function by undertaking an RNA interference screen in a sensitized genetic background to identify genes required for PC activity. In addition to this genetic screen, I will identify meiotic chromosomal proteins proteomically by comparing the protein profiles of nuclei isolated from wildtype worms and mutant worms that lack a germline. Molecular factors identified by these complementary approaches will be further characterized to determine their roles in homolog pairing and synapsis.
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0.943 |
2007 — 2010 |
Bhalla, Needhi |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Characterization of the Synapis Checkpoint in C. Elegans Meiosis @ University of California Berkeley
[unreadable] DESCRIPTION (provided by applicant): Meiosis generates haploid gametes from a diploid cell such that a diploid genome is restored upon fertilization. The proper segregation of chromosomes during the meiotic divisions depends on events in meiotic prophase, such as the pairing and synapsis of homologous chromosomes and crossover recombination. Errors in chromosome segregation are usually fatal to the fertilized zygote but can also result in cancer predisposition or serious developmental disorders. I have identified a meiotic checkpoint that responds to defects in homolog synapsis, independent of a DNA damage/recombination checkpoint, and activates apoptosis to avoid the generation of aneuploid gametes. Not all unsynapsed sequences have the capacity to trigger this checkpoint; rather, this pathway is specifically activated by unsynapsed pairing centers (PCs), chromosome sites that promote synapsis in C. elegans. Furthermore, the checkpoint requires the C. elegans homolog of PCH-2, a budding yeast pachytene checkpoint gene, suggesting that the molecular mechanism that detects synaptic failure is widely conserved. [unreadable] [unreadable] I plan to further characterize this synapsis checkpoint. I am particularly interested in the PC's contribution to synapsis checkpoint activation. The identification and characterization of proteins that interact with factors required for PC function will provide insight into how this locus activates the checkpoint when unsynapsed. Studies that address the regulation of heterochromatin on unsynapsed chromosomes and how the PC may inhibit the DNA damage checkpoint will also be undertaken. I will determine the role of the synaptonemal complex (SC) in the synapsis checkpoint by characterizing two genes that interact with the SC and appear to be required for the checkpoint by preliminary RNA inteferference (RNAi) experiments. I will investigate the function and regulation of the known checkpoint component, pch-2; a GFP-PCH-2 fusion protein will be localized in a variety of genetic backgrounds and a reagent will be provided to identify interacting proteins biochemically. Furthermore, I will identify additional components of the checkpoint by undertaking an RNAi screen that will focus on candidate genes that fulfill specific expression and phenotypic profile criteria. These complementary approaches will enable me to gain a molecular and mechanistic understanding of how homolog synapsis is monitored and how an unsynapsed or inappropriately synapsed homolog generates a checkpoint signal that is ultimately translated into an apoptotic response. [unreadable] [unreadable] Meiosis produces gametes, such as eggs and sperm. Checkpoints monitor meiotic events to ensure that gametes have the correct number of chromosomes. If a gamete has an incorrect number of chromosomes, the embryo that results from fertilization is often inviable. Occasionally, an embryo inherits an extra chromosome that is not lethal but can cause cancer predisposition or serious developmental defects. [unreadable] [unreadable] [unreadable]
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0.976 |
2011 — 2016 |
Bhalla, Needhi |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Synapsis Checkpoint in C. Elegans Meiosis @ University of California Santa Cruz
DESCRIPTION (provided by applicant): Meiosis generates haploid gametes, such as sperm and eggs, from a diploid cell such that a diploid genome is restored upon fertilization. The proper segregation of chromosomes during the meiotic divisions depends on events in meiotic prophase, such as synapsis of homologous chromosomes and crossover recombination. Errors in chromosome segregation are usually fatal to the fertilized zygote but can also result in cancer predisposition or developmental disorders. We have identified a meiotic checkpoint that responds to defects in homolog synapsis, independent of a DNA damage/recombination checkpoint, and activates apoptosis to avoid the generation of aneuploid gametes. Not all unsynapsed sequences have the capacity to trigger this checkpoint;rather, this pathway is specifically activated by unsynapsed Pairing Centers (PCs), chromosome sites that promote synapsis in C. elegans. Furthermore, the checkpoint requires the C. elegans homolog of PCH2, a budding yeast meiotic checkpoint gene, suggesting that the molecular mechanism that detects synaptic failure is conserved. Using a combination of genetic, biochemical and cytological approaches, we plan to further investigate the synapsis checkpoint. We will address how chromatin state(s) contributes to the ability of PCs to activate the synapsis checkpoint by studying the role of chromatin-modifying enzymes at these cis-acting sites. We will determine how the assembly of the synaptonemal complex (SC) is monitored during a normal meiosis by localizing PCH-2 in wildtype and mutant backgrounds, identifying proteins that interact with PCH-2 and investigating whether PCH-2 specifically modifies an important class of SC components. Furthermore, we will identify additional components of the checkpoint by undertaking an RNA interference screen that will focus on candidate genes that fulfill specific expression and phenotypic profile criteria. This screen has identified a putative transcription factor as a checkpoint component and we will test whether this factor directly regulates the core apoptotic machinery in response to checkpoint activation. These complementary approaches will enable us to gain a molecular and mechanistic understanding of how homolog synapsis is monitored during meiosis and how an unsynapsed or inappropriately synapsed homolog generates a checkpoint signal that is ultimately translated into an apoptotic response to avoid the production of aneuploid gametes. PUBLIC HEALTH RELEVANCE: Meiosis produces gametes, such as eggs and sperm. Checkpoints monitor meiotic events to ensure that gametes have the correct number of chromosomes. If a gamete has an incorrect number of chromosomes, the embryo that results from fertilization is often inviable. Occasionally, an embryo inherits an extra chromosome that is not lethal but can cause birth defects. An investigation of meiotic checkpoints can reveal general mechanisms that ensure genomic integrity.
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0.973 |
2017 — 2020 |
Bhalla, Needhi |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulating and Monitoring Meiotic Synapsis in C. Elegans @ University of California Santa Cruz
Project Summary Meiosis generates haploid gametes, such as sperm and eggs, from a diploid cell such that a diploid genome is restored upon fertilization. The proper segregation of chromosomes during the meiotic divisions relies on events in meiotic prophase, such as synapsis of homologous chromosomes and crossover recombination. Errors in chromosome segregation are usually fatal to the fertilized zygote but can also result in cancer predisposition or developmental disorders. In C. elegans, a meiotic checkpoint monitors homolog synapsis, independent of a DNA damage/recombination checkpoint, and activates apoptosis to avoid the generation of aneuploid gametes. This checkpoint depends on Pairing Centers (PCs), chromosome sites that act as sites for synapsis initiation. PCs promote synapsis by nucleating structures at the nuclear envelope to gain access to cytoplasmic microtubules and mobilize chromosomes. Since PCs mediate microtubule attachment and are regulatory platforms for checkpoints that monitor chromosome behavior, PCs have been compared to centromeres. Although the cytoskeletal-mediated mobilization of chromosomes is a common feature of meiotic prophase, its specific function during synapsis is not well understood. Our initial studies of this meiotic checkpoint have revealed that the monitoring and regulation of homolog synapsis are mechanistically linked: components of this checkpoint are also required to mediate synapsis. We have also uncovered a surprising connection between the synapsis checkpoint and the mitotic spindle checkpoint. Using a combination of genetic, biochemical and cytological approaches, we plan to further investigate this link between synapsis initiation, synapsis checkpoint activation and PC function. We will answer the following questions: 1) Do factors required for the synapsis checkpoint regulate PC movement to inhibit synapsis initiation? 2) What functions of MAD-1 and MAD-2 are required to regulate and monitor synapsis? 3) Does the conserved protein Shugoshin define a new pathway to regulate and monitor synapsis? Given that the mobilization of chromosomes during meiotic prophase is conserved, it is likely that our studies will provide important information about the regulation of synapsis even in systems that do not rely on PCs for synapsis.
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0.973 |
2018 — 2021 |
Bhalla, Needhi Hartzog, Grant (co-PI) [⬀] Abrahamsson, Sara [⬀] Sullivan, William |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Nsf Mri: Development of a Multifocus Structured Illumination Microscope @ University of California-Santa Cruz
An award is made to the University of California, Santa Cruz to develop and construct a groundbreaking new imaging system for live 3D super-resolution microscopy and employ this instrument to study the dynamic processes of life beyond the classical resolution limit (~ 200 nm). The instrument will employ Multifocus Structured Illumination Microscopy, a transformative new imaging technique. The project team will construct and employ this powerful 3D super-resolution imaging system in the University of California at Santa Cruz (UCSC) Life Sciences Microscopy Center in collaboration with biology research groups with an initial focus on studying chromatin dynamics. Our DNA genomes are stored in the nucleus of cells as a protein-DNA complex known as chromatin. The basic repeating subunit of chromatin, the nucleosome, consists of a protein core with DNA wrapped twice around its outside, like thread around a spool. Our DNA genomes are organized into millions of regularly spaced nucleosomes which allow our DNA to be stored compactly and create new opportunities for regulation of gene expression.
Multifocus Structured Illumination Microscopy is designed to enable 3D imaging of chromatin in living cells at nearly physiological conditions with super-resolution capability. Using specially designed diffractive optical components, which will be custom made by the project team in one of the University of California academic nanofabrication user facilities, the microscope will simultaneously capture, on a single camera, an entire 3D volume of the biological specimen, by multiplexing and focus shifting the beam of light exiting the microscope objective. Employing fast Structured Illumination super-resolution imaging, the microscope will furthermore provide improved contrast and resolution to allow visualization of structures smaller than 200 nm, which have classically been impossible to study in living specimens. Placement of this instrument in the UCSC Life Sciences Microscopy Center ensures direct availability of new and exciting optical technology for application in biological research. The microscope will open up new fields of research, initially in chromatin dynamics, and successively also in other fields of biological research, where live 3D imaging beyond the classical limit of resolution is needed.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
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0.973 |
2021 |
Bhalla, Needhi |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
Cell Cycle Checkpoint Control in C. Elegans @ University of California Santa Cruz
Project Summary Chromosome segregation is precisely controlled to ensure that daughter cells receive the correct number of chromosomes. Cell cycle checkpoints play an important role in this regulation by monitoring chromosome behavior and delaying or arresting the cell cycle to correct errors. Despite being characterized almost exclusively in single cells, the functions of cell cycle checkpoints are perhaps most critical in multicellular organisms, where chromosomal abnormailities can produce cancer, infertility, miscarriages and birth defects. As multicellular organisms develop, cells undergo dramatic changes in size, shape, fate, chromosome structure and cell cycle duration. How the function of cell cycle checkpoints is coordinated with and modulated by these changes in cellular context are unknown. We have shown that checkpoint proteins in one biological context can monitor and regulate radically different chromosome behaviors in a different biological context. By analyzing the function and regulation of essential checkpoint factors in cells that vary in size, shape, fate, and tissue in C. elegans, we will identify mechanisms, both common and unique, that guarantee that chromosomes segregate properly in all cell types. Fundamentally, our future work is focused on addressing two major questions: Does the function of checkpoint proteins vary depending on their biological context, such that the same proteins appear to have dramatically different roles? Or are there common fundamental mechanisms that monitor diverse chromosome behaviors to produce functionally different checkpoint responses?
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0.973 |
2021 |
Bhalla, Needhi |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training Program in Molecular, Cell, and Developmental Biology @ University of California Santa Cruz
PROJECT SUMMARY / ABSTRACT The graduate Training Program in Molecular, Cell and Developmental Biology (MCDB) is a student- centered interdisciplinary training program that includes 29 principal investigators from 5 departments, with 76 PhD students currently in training. The MCDB program is 1 of 4 training tracks within a larger umbrella program called the Program in Biomedical Sciences and Engineering (PBSE), which encom- passes investigators who study diverse topics in biomedical science. Students admitted into the MCDB Training Program can do research rotations with any of the PBSE faculty, thereby gaining opportunities to explore diverse research topics and methodologies. MCDB students take courses designed to foster independent and critical thinking, as well as an understand- ing of key principles of biomedical science. The courses instruct students in rigor and reproducibility and build basic competencies needed for success in diverse careers. In addition to the core courses, students take an ethics course, a grant writing course, a pedagogy course, a career planning course, and elective courses. The Program Director, a Thesis Advisory Committee, and the Graduate Advis- ing Committee closely monitor student progress and intervene as necessary to ensure retention and successful completion of the program. The average time to degree is 5.9 years. The most motivated and promising MCDB students are selected for Training Grant support based on their academic records and their engagement and performance in core courses and research rota- tions. Training Grant students are usually selected soon after they join a thesis lab for support in Years 2-3. Support is requested for 12 students per year, but we note that all students in our program benefit from the high standards and goals of NIH-supported graduate programs and the innovations in mentoring and training that we have implemented to meet those standards and goals. The MCDB Training Program can point to a number of important achievements. An ambitious and highly successful effort to build an inclusive and diverse program has allowed us to reach 30% URM students in training, as well as a training faculty that is greater than 50% women. We closely track career outcomes for our students, which shows that 73% of our graduates over the last 13 years have gone on to successful careers in the sciences and an additional 20% are training as postdocs. With support from the NIH, we created an exciting new Career Planning course that equips students with the skills and inspiration to pursue diverse careers. A complete restructuring of our core courses has kept them current and relevant. Together, these kinds of innovations have helped drive the success of our training program, which produces outstanding graduates who bring unique skills and diversity to the national biomedical science workforce.
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0.973 |