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Neuromodulation and Neurodegeneration: the Missing Link and Mechanisms of Action

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

SIEBER, BETH-ANNE

项目受资助机构

CALIFORNIA INSTITUTE OF TECHNOLOGY

项目编号

3DP2NS087949-02S1

立项年度

2019

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

1080374.00美元

学科

Assistive Technology;Bioengineering;Brain Disorders;Neurodegenerative;Neurosciences;Parkinson's Disease;Rehabilitation

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

GRADINARU, VIVIANA

参与机构

NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

项目标书摘要：Neurodegeneration has proven notoriously difficult to study and there is currently no proven or acceptable method to prevent or slow down the course of disease in humans. A very successful intervention for Parkinson?s disorder (PD) is neuromodulation via deep brain stimulation (DBS). DBS successfully restores motor function but what DBS does to the course of the disease is very poorly understood. Intriguingly, a few rodent model studies and clinical observations suggest that DBS could be neuroprotective, but because current practice is to implant the electrodes late in the progression of the disease, neuroprotective effects of electrical stimulation have been challenging to document. It is therefore vital that we are not missing on a crucial opportunity for neurological patients and research the causal links, mechanisms, and timelines associated with neuroprotection via neuromodulation. I propose an interdisciplinary approach for which I am uniquely trained that uses optogenetics, electrophysiology, biochemistry, and collaborative device engineering to study the interplay between neuronal health and brain circuit activity in intact behaving rodents. Specifically, I propose to study the factors influencing the function and health of dopaminergic neurons in the brain and their role in animal behavior. Our findings could allow us to positively interfere with cells such as the dopaminergic neurons in the substantia nigra pars compacta (SNc) that degenerate and die in PD. Below I list 3 specific challenges that I will tackle using innovative, interdisciplinary, approaches. 1. Are all SNc dopaminergic neurons equally impactful on behavior or are there hotspots where cells, due to their heterogeneous electrical and neurochemical characteristics and connectivity, can maximally interfere with behavior when degenerated? 2. Once dopaminergic degeneration starts, can neurodegeneration be halted or slowed down by altering the activity of defined brain circuits? I will test this intriguing hypothesis by performing chronic optogenetic control of inputs to the SNc and measure changes in the degeneration rate. 3. Is growth factor signaling directly contributing to dopaminergic neuroprotection and what are the timelines needed for neuroprotection? Previous experiments applied growth factors liberally in a non-specific fashion and/or with poor temporal resolution. I will develop optogenetic methods to achieve cell-type specific control of growth factor signaling so I can directly probe the protective role of growth factors in defined cell types, and especially cells prone to degeneration. These tools could also be applied to research beyond the nervous system since growth factor signaling is involved in key cellular phenomena such gene transcription that can impact the cell survival, differentiation, and function. Together these innovative projects will contribute to my long-term goals of building cellular resilience via neuromodulation and have a paradigm-shifting impact in neurodegeneration research.

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  • 1.Viral Strategies for Targeting the Central and Peripheral Nervous Systems

    • 关键词：
    • RECOMBINANT-ADENOASSOCIATED-VIRUS; DRIVE SELECTIVE EXPRESSION; BLOOD-BRAIN-BARRIER; GENE-THERAPY; NONHUMAN-PRIMATES; TRANSGENE EXPRESSION; RABIES VIRUS; MOUSE-BRAIN; SPINAL-CORD; IN-VIVO
    • Bedbrook, Claire N.;Deverman, Benjamin E.;Gradinaru, Viviana
    • 《ANNUAL REVIEW OF NEUROSCIENCE, VOL 41》
    • 2018年
    • 会议

    Recombinant viruses allow for targeted transgene expression in specific cell populations throughout the nervous system. The adeno-associated virus (AAV) is among the most commonly used viruses for neuroscience research. Recombinant AAVs (rAAVs) are highly versatile and can package most cargo composed of desired genes within the capsid's similar to 5-kb carrying capacity. Numerous regulatory elements and intersectional strategies have been validated in rAAVs to enable cell type-specific expression. rAAVs can be delivered to specific neuronal populations or globally throughout the animal. The AAV capsids have natural cell type or tissue tropism and trafficking that can be modified for increased specificity. Here, we describe recently engineered AAV capsids and associated cargo that have extended the utility of AAVs in targeting molecularly defined neurons throughout the nervous system, which will further facilitate neuronal circuit interrogation and discovery.

    ...

  • 2.Hydrogel-Tissue Chemistry:Principles and Applications

    • 关键词：
    • SINGLE-CELL RESOLUTION; INTACT-TISSUE; 3-DIMENSIONAL VISUALIZATION; MOLECULAR INTERROGATION; LIGHT-MICROSCOPY; BRINGING CLARITY; CLEARING AGENT; WHOLE-BRAIN; MOUSE; PROTEINS
    • Gradinaru, Viviana;Treweek, Jennifer;Overton, Kristin;Deisseroth, Karl
    • 《ANNUAL REVIEW OF BIOPHYSICS, VOL 47》
    • 2018年
    • 会议

    Over the past five years, a rapidly developing experimental approach has enabled high-resolution and high-content information retrieval from intact multicellular animal (metazoan) systems. New chemical and physical forms are created in the hydrogel-tissue chemistry process, and the retention and retrieval of crucial phenotypic information regarding constituent cells and molecules (and their joint interrelationships) are thereby enabled. For example, rich data sets defining both single-cell-resolution gene expression and single-cell-resolution activity during behavior can now be collected while still preserving information on three-dimensional positioning and/or brain-wide wiring of those very same neurons-even within vertebrate brains. This new approach and its variants, as applied to neuroscience, are beginning to illuminate the fundamental cellular and chemical representations of sensation, cognition, and action. More generally, reimagining metazoans as metareactants-or positionally defined three-dimensional graphs of constituent chemicals made available for ongoing functionalization, transformation, and readout-is stimulating innovation across biology and medicine.

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